United States Government Accountability Office

GAO Report to Congressional Requesters

FOOD AND DRUG 

ADMINISTRATION 

Decision Process to 

Deny Initial 

Application for 

Over-the-Counter 

Marketing of the 

Emergency 

Contraceptive Drug 

Plan B Was Unusual 

November 2005 

 

GAO-06-109 
What GAO Found

United States Government Accountability Office

Why GAO Did This Study

Highlights

Accountability Integrity Reliability

November 2005

FOOD AND DRUG ADMINISTRATION

Decision Process to Deny Initial 

Application for Over-the-Counter 

Marketing of the Emergency 

Contraceptive Drug Plan B Was Unusual 

Highlights of GAO-06-109, a report to 

congressional requesters 

In April 2003, Women’s Capital 

Corporation submitted an 

application to the Food and Drug 

Administration (FDA) requesting

the marketing status of its 

emergency contraceptive pill

(ECP), Plan B, be switched from 

prescription to over-the-counter 

(OTC). ECPs can be used to 

prevent an unintended pregnancy 

when contraception fails or after 

unprotected intercourse, including 

cases of sexual assault. In May 

2004, the Acting Director for the 

Center for Drug Evaluation and 

Research (CDER) issued a “notapprovable” letter for the switch 

application, citing safety concerns 

about the use of Plan B in women 

under 16 years of age without the 

supervision of a health care 

practitioner. Because the notapprovable decision for the Plan B 

OTC switch application was 

contrary to the recommendations 

of FDA’s joint advisory committee 

and FDA review staff, questions 

were raised about FDA’s process 

for arriving at this decision. GAO 

was asked to examine (1) how the 

decision was made to not approve 

the switch of Plan B from 

prescription to OTC, (2) how the 

Plan B decision compares to the 

decisions for other proposed 

prescription-to-OTC switches from 

1994 through 2004, and (3) whether 

there are age-related marketing 

restrictions for prescription Plan B 

and other prescription and OTC 

contraceptives. To conduct this 

review, GAO examined FDA’s 

actions prior to the May 6, 2004, 

not-approvable letter for the initial 

application. 

On May 6, 2004, the Acting Director of CDER rejected the recommendations 

of FDA’s joint advisory committee and FDA review officials by signing the 

not-approvable letter for the Plan B switch application. While FDA followed 

its general procedures for considering the application, four aspects of FDA’s 

review process were unusual. First, the directors of the offices that reviewed 

the application, who would normally have been responsible for signing the 

Plan B action letter, disagreed with the decision and did not sign the notapprovable letter for Plan B. The Director of the Office of New Drugs also 

disagreed and did not sign the letter. Second, FDA’s high-level management 

was more involved in the review of Plan B than in those of other OTC switch 

applications. Third, there are conflicting accounts of whether the decision to 

not approve the application was made before the reviews were completed. 

Fourth, the rationale for the Acting Director’s decision was novel and did not 

follow FDA’s traditional practices. The Acting Director stated that he was 

concerned about the potential behavioral implications for younger 

adolescents of marketing Plan B OTC because of their level of cognitive

development and that it was invalid to extrapolate data from older to 

younger adolescents. FDA review officials noted that the agency has not 

considered behavioral implications due to differences in cognitive 

development in prior OTC switch decisions and that the agency previously

has considered it scientifically appropriate to extrapolate data from older to 

younger adolescents. 

The Plan B decision was not typical of the other 67 proposed prescription-toOTC switch decisions made by FDA from 1994 through 2004. The Plan B 

OTC switch application was the only one during this period that was not 

approved after the advisory committees recommended approval. The Plan B 

action letter was the only one signed by someone other than the officials 

who would normally sign the letter. Further, there are no age-related 

marketing restrictions for any prescription or OTC contraceptives that FDA 

has approved, and FDA has not required pediatric studies for them. FDA

identified no issues that would require age-related restrictions in the review 

of the original prescription Plan B new drug application. 

In its comments on a draft of this report, FDA disagreed with GAO’s finding 

that high-level management was more involved with the Plan B OTC switch 

application than usual, with GAO’s discussion about when the notapprovable decision was made, and with GAO’s finding that the Acting 

Director of CDER’s rationale for denying the application was novel. 

However, GAO found that high-level management’s involvement for the Plan 

B decision was unusual for an OTC switch application and FDA officials 

gave GAO conflicting accounts about when they believed the decision was 

made. The Acting Director acknowledged to GAO that considering 

adolescents’ cognitive development as a rationale for a not-approvable

decision was unprecedented for an OTC application, and other FDA officials 

told GAO that the rationale differed from FDA’s traditional practices. 

www.gao.gov/cgi-bin/getrpt?GAO-06-109.

To view the full product, including the scope 

and methodology, click on the link above. 

For more information, contact Marcia Crosse 

at (202) 512-7119 or crossem@gao.gov. 
Contents 

Letter 1

Results in Brief 5 

Background 7

Aspects of FDA’s Review of the Plan B Switch Application Were 

Unusual 13

Plan B Decision Was Not Typical of Other Proposed Prescriptionto-OTC Switch Decisions 29 

There Are No Age-Related Restrictions for Safety Reasons for Any 

FDA-Approved Contraceptives 30 

Agency Comments and Our Evaluation 31 

Appendix I Scope and Methodology 36 

Appendix II Not-Approvable Letter for the Prescription-to-OTC 

Switch Application of Plan B, May 6, 2004 38 

Appendix III Timeline of Major Plan B Events Related to the Initial 

OTC Switch Application 42 

Appendix IV Acting Director of CDER’s Official Memorandum 

Explaining His Not-Approvable Decision, May 6, 2004 47 

Appendix V Director of the Office of New Drugs’ Official 

Memorandum on His Decision on the Plan B 

Application, April 22, 2004 50 

Appendix VI Comments from the Food and Drug Administration 53 

Appendix VII GAO Contact and Staff Acknowledgments 57 

 

Page i GAO-06-109 Initial FDA Decision on Emergency Contraceptive
Table 

Table 1: Brief Timeline of Major Plan B Events Related to the Initial 

OTC Switch Application 15 

Figure 

Figure 1: Flow of an OTC Switch Application through the Decision 

Process within CDER for First-in-a-Class Drug 9 

Abbreviations 

ACRHD Advisory Committee for Reproductive Health Drugs 

CDER Center for Drug Evaluation and Research 

ECP emergency contraceptive pill 

FDA Food and Drug Administration 

NDA new drug application 

NDAC Nonprescription Drugs Advisory Committee 

OTC over-the-counter 

PDUFA Prescription Drug User Fee Act 

PREA Pediatric Research Equity Act 

sNDA supplemental new drug application

STD sexually transmitted disease 

WCC Women’s Capital Corporation 

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Page ii GAO-06-109 Initial FDA Decision on Emergency Contraceptive
United States Government Accountability Office

Washington, DC 20548 

November 14, 2005 

Congressional Requesters

In April 2003, Women’s Capital Corporation (WCC) submitted an 

application to the Food and Drug Administration (FDA) requesting that 

the marketing status of its emergency contraceptive pill (ECP), Plan B, be 

switched from prescription to over-the-counter (OTC).1

 ECPs can be used 

to prevent unintended pregnancy when contraception fails or after 

unprotected intercourse, including cases of sexual assault. Plan B had 

been approved for use as a prescription drug by FDA in 1999 and is most 

effective when taken as soon as possible, but no later than 72 hours, after 

intercourse. By law, FDA may approve the switch of a prescription drug to 

OTC status if use of the drug is safe and effective for self-medication in 

accordance with proposed labeling.2

 Since 1975, when FDA formalized the 

current process for approving prescription-to-OTC switches, FDA has 

approved approximately 90 applications to change the marketing status of 

a prescription drug to OTC. 

According to FDA’s operational policies, reviews of OTC switch 

applications occur in its Center for Drug Evaluation and Research 

(CDER).3

 OTC switch applications for drugs that are “first-in-a-class,”4

such as Plan B, are reviewed by two of the six offices of drug evaluation 

within CDER—including the Office of Drug Evaluation V, which reviews 

all OTC switch applications, and the office of drug evaluation that has the 

relevant expertise for the proposed switch drug.5

 In addition, CDER can 

request a joint meeting of advisory committees that it has established to 

 1

FDA defines prescription-to-OTC switch as the OTC marketing of a product that was once 

a prescription drug product for the same indication, strength, dose, duration of use, dosage 

form, population, and route of administration. In this report, the phrase “OTC switch” 

refers to a prescription-to-OTC switch. 

2

See 21 U.S.C. § 353(b)(1); 21 C.F.R. § 310.200(b) (2005). 

3

FDA’s operational policies are in its manuals of policies and procedures.

4

A class of drugs refers to a category based on the chemical ingredients of the drugs. “Firstin-a-class” refers to the first drug to be reviewed for an OTC switch within a class of drugs. 

5

In this report, FDA review staff refers to the staff in the Offices of Drug Evaluation III and

V who reviewed the Plan B OTC switch application. The CDER structure described in this

report is the one that existed at that time. 

Page 1 GAO-06-109 Initial FDA Decision on Emergency Contraceptive
seek scientific advice about its decisions from outside experts. The joint 

advisory committee meeting is conducted by the advisory committee that 

has expertise in OTC drugs and the advisory committee that has relevant

expertise for the proposed OTC switch drug. After review of the OTC 

switch application and advice of the joint advisory committee, the 

directors of both offices of drug evaluation make a decision. If the 

directors of the offices concur on the decision for the application, they 

generally will both sign and issue an action letter.6

 If the directors do not 

concur with one another, the application is sent to the next level of review, 

the Director of the Office of New Drugs within CDER, who then makes the 

decision and signs and issues the action letter. However, the Director of 

CDER can also decide on an application and sign and issue the action 

letter. 

The Plan B application went to the Office of Drug Evaluation V, which 

includes the Division of Over-the-Counter Drug Products, and the Office of 

Drug Evaluation III, which includes the Division of Reproductive and 

Urologic Drug Products, where it was reviewed. In December 2003, a joint

meeting of two FDA advisory committees, the Nonprescription Drugs 

Advisory Committee (NDAC) and the Advisory Committee for 

Reproductive Health Drugs (ACRHD), recommended in a vote of 23 to 4 

that the proposed OTC switch for Plan B be approved. FDA review staff 

also agreed that Plan B should be granted OTC status. On May 6, 2004, the 

Acting Director of CDER7

 signed a “not-approvable” letter for the switch to 

 6

An action letter is a written communication to the sponsor from FDA stating the outcome

of the review of an application. The sponsor or applicant is the person or entity that 

assumes responsibility for the marketing of a new drug, including responsibility for 

compliance with applicable provisions of the Federal Food, Drug, and Cosmetic Act and

related regulations. 

7

The current Director of CDER was appointed to this position on July 29, 2005. However,

he held the title of Acting Director from fall 2003 until his appointment. Prior to his

appointment to Acting Director, he was Deputy Director of CDER. Because he was Acting 

Director during most of the time covered by this report—for those events associated with 

the initial Plan B OTC switch application through the May 6, 2004, decision—we use the

title of Acting Director for him in this report. 

Page 2 GAO-06-109 Initial FDA Decision on Emergency Contraceptive
OTC,8

 citing safety concerns about the use of Plan B in women under 16 

years of age without the supervision of a practitioner licensed by law to 

administer the drug.9

 On July 22, 2004, Barr Pharmaceuticals, Inc.,10

submitted an amended application for the proposed Plan B switch to 

market Plan B OTC for women 16 years of age and older and as a 

prescription drug for those under 16 years of age.11

Because the not-approvable decision for the initial Plan B OTC switch 

application was contrary to the recommendations of the joint advisory 

committee and the FDA review staff, you raised questions about FDA’s 

process for arriving at its decision on the initial application. In this report, 

for the initial Plan B OTC switch application, we examined (1) how the 

decision was made to not approve the switch of Plan B from prescription 

to OTC, (2) how the Plan B decision compares to the decisions for other 

proposed prescription-to-OTC switches from 1994 through 2004, and (3) 

 8

A not-approvable letter is a letter to the sponsor from FDA stating that the agency does not 

consider the application approvable because of one or more deficiencies in the application. 

See 21 C.F.R. § 314.120. There are two other types of action letters: the approval letter and 

the approvable letter. The approval letter indicates that the application is approved and the 

drug may go OTC. An approvable letter is similar to the not-approvable letter in that there 

are one or more deficiencies in the application precluding its approval. See 21 C.F.R. §

314.110. FDA officials stated that the difference between a not-approvable letter and an 

approvable letter is that a not-approvable letter is generally issued when more studies are

required and an approvable letter is generally issued if there are sufficient data, but some

outstanding concerns still exist. 

9

Besides physicians, other health care providers, such as nurse practitioners and 

physicians’ assistants, may be licensed by law to administer drugs. While only FDA may 

change a drug’s status from prescription to OTC, the practice of pharmacy is state 

controlled, allowing each state to decide who may prescribe a drug. While most states do 

not allow pharmacists to prescribe drugs, eight states (Alaska, California, Hawaii, Maine, 

Massachusetts, New Hampshire, New Mexico, and Washington) allow pharmacists to 

prescribe ECPs or provide them in accordance with approved physician protocols.

10In February 2004, WCC sold the rights to market Plan B to Barr Pharmaceuticals, Inc. In 

October 2003, as the purchase of Plan B by Barr Pharmaceuticals, Inc., was being finalized, 

Barr began acting as the agent for WCC regarding Plan B.

11On August 26, 2005, FDA announced it had completed its review of the amended

application and concluded that the scientific data were sufficient to support the safe use of 

Plan B in an OTC setting for women 17 years of age and older. However, FDA delayed 

taking action on the amended application to seek public comment on marketing issues 

related to this decision. See also Drug Approvals: Circumstances Under Which an Active 

Ingredient May Be Simultaneously Marketed in Both a Prescription Drug Product and an 

Over-the-Counter Drug Product, 70 Fed. Reg. 52050 (2005). Accordingly, as of November 4, 

2005, Plan B may not be legally marketed OTC. 

Page 3 GAO-06-109 Initial FDA Decision on Emergency Contraceptive
whether there are age-related marketing restrictions for prescription Plan

B and other prescription and OTC contraceptives. 

To address our objectives, we examined documents, including the official 

minutes from meetings of FDA staff and the written reviews of the 

adequacy of the Plan B OTC switch application prepared by FDA staff in 

the Offices of Drug Evaluation III and V and the Office of New Drugs, 

related to the review of, and decision on, the Plan B OTC switch 

application, and we interviewed FDA staff and officials who conducted the 

reviews and were involved in the decision. We also reviewed FDA’s 

manuals of policies and procedures and The CDER Handbook to 

determine how FDA considers an application to switch a drug from 

prescription to OTC.12 We interviewed members of FDA’s two advisory 

committees that met jointly to discuss the Plan B OTC switch application,

and we reviewed the transcript of its meeting. We compared the FDA 

decision for Plan B to FDA’s decisions for other proposed prescription-toOTC switch applications from 1994 through 2004. We interviewed officials 

from Barr Pharmaceuticals, Inc., the company currently sponsoring the 

Plan B application for the prescription-to-OTC switch, and WCC, the 

original sponsor of the Plan B switch application. In addition, we reviewed 

documents and interviewed FDA officials regarding age-related marketing 

restrictions for prescription Plan B and other prescription and OTC 

contraceptives. We also interviewed representatives from the American 

College of Obstetricians and Gynecologists, the American Academy of 

Pediatrics, Concerned Women for America, and the Planned Parenthood 

Federation of America, Inc., regarding FDA’s safety concerns for Plan B 

and other contraceptives. Our work examined only events and

communications within FDA and between FDA and the Plan B sponsor; 

we did not consider any communications that may have occurred between

FDA officials and other executive agencies. Our work examined only 

FDA’s actions prior to the May 6, 2004, not-approvable letter for the initial 

application, and we did not examine aspects of FDA’s subsequent 

deliberations about Plan B. (See app. I for details regarding our scope and 

methodology and app. II for a copy of the May 6, 2004, not-approvable 

letter for the initial application.) We conducted our work from September 

2004 through November 2005 in accordance with generally accepted

government auditing standards. 

 12The CDER Handbook contains information on the center’s processes and activities. It was 

created for industry officials, health professionals, academics, and the general public, and 

it is available at www.fda.gov/cder/handbook/startpag.htm (downloaded Dec. 8, 2004).

Page 4 GAO-06-109 Initial FDA Decision on Emergency Contraceptive
On May 6, 2004, the Acting Director of CDER rejected the 

recommendations of the joint advisory committee and FDA review 

officials by signing the not-approvable letter for the Plan B switch 

application, concluding a review process that began on April 16, 2003, 

when WCC submitted a standard supplemental new drug application 

(sNDA) requesting that Plan B be made available without a prescription. 

While FDA followed its general procedures for considering the 

application, four aspects of FDA’s review process were unusual. First, the 

Directors of the Offices of Drug Evaluation III and V, who would normally 

have been responsible for signing the Plan B action letter, disagreed with 

the decision and did not sign the not-approvable letter for Plan B. The 

Director of the Office of New Drugs also disagreed and did not sign the 

letter. Second, FDA’s high-level management was more involved in the 

review of Plan B than in those of other OTC switch applications. For 

example, FDA review staff told us that they were told early in the review 

process that the decision would be made by high-level management. Third, 

as documented in the reviews of FDA staff and in our interviews with FDA 

officials, there are conflicting accounts of whether the decision to not 

approve the application was made before the reviews were completed. 

Fourth, the rationale for the Acting Director of CDER’s decision was novel 

and did not follow FDA’s traditional practices. Specifically, the Acting 

Director was concerned about the potential impact that the OTC 

marketing of Plan B would have on the propensity for younger adolescents 

to engage in unsafe sexual behaviors because of their lack of cognitive 

maturity compared to older adolescents. He also stated that it was invalid 

to extrapolate data from older to younger adolescents in this case. FDA 

review officials noted that the agency has not considered behavioral 

implications due to differences in cognitive development in prior OTC 

switch decisions and that the agency has considered it scientifically 

appropriate to extrapolate data from older to younger adolescents. 

Results in Brief 

The decision to not approve the Plan B OTC switch application was not 

typical of the other 67 prescription-to-OTC switch decisions made from 

1994 through 2004. FDA’s joint advisory committee considered 23 OTC 

switch applications during this period; the Plan B OTC switch application 

was the only 1 of those 23 that was not approved after the joint committee 

voted to recommend approval of the application. Also, the Plan B action 

letter was the only one signed by the Director of CDER, in this case the 

Acting Director of CDER, instead of the directors of the offices or 

divisions that reviewed the application, who would normally sign an action 

letter. 

Page 5 GAO-06-109 Initial FDA Decision on Emergency Contraceptive
There are no age-related marketing restrictions for safety reasons for any 

of the prescription or OTC contraceptives that FDA has approved, and 

FDA has not required pediatric studies for them. All FDA-approved OTC 

contraceptives are available to anyone, and all FDA-approved prescription 

contraceptives are available to anyone with a prescription. For hormonal 

contraceptives, FDA assumes that suppression of ovulation would be the 

same for any female after menarche,

13 regardless of age. FDA did not 

identify any issues that would require age-related restrictions in its review

of the original application for prescription Plan B, and prescription Plan B

is available to women of any age. 

In its comments on a draft of this report, FDA disagreed with three of our 

findings. First, FDA disagreed with our finding that the involvement of 

high-level management in the Plan B decision was unusual because their 

involvement is likely in high-profile and controversial regulatory decisions. 

Although we agree that high-level management involvement is more likely 

to occur with high-profile regulatory decisions, we found that the level of 

high-level management involvement for the Plan B decision was unusual 

for OTC switch applications. The other examples of high-level

management involvement given to us by FDA officials during the course of 

our work involved decisions about the marketing of prescription drugs. 

Second, FDA disagreed with our discussion about when the decision to 

deny the switch application was made. We maintain that the draft report 

accurately noted that FDA officials gave us conflicting accounts about 

when they believed the not-approvable decision was made. Third, FDA 

disagreed with our finding that the Acting Director of CDER’s rationale for

denying the application was novel and did not follow FDA’s traditional 

practices. We found that the Acting Director’s rationale was novel because

it explicitly considered the differing levels of cognitive maturity of 

adolescents of different ages, and that, because of the Acting Director’s 

views about these differences in cognitive maturity, he concluded that it 

was inappropriate to extrapolate data related to risky sexual behavior 

from older to younger adolescents. The Acting Director acknowledged to

us that considering adolescents’ cognitive development as a rationale for a 

not-approvable decision was unprecedented for an OTC application. In 

addition, other FDA officials told us that the agency had not previously 

considered whether younger adolescents would use a product differently

than older adolescents. Therefore, we believe that our finding is correct

 13Menarche is the initial menstrual period, normally occurring between a female’s 9th and 

17th year. 

Page 6 GAO-06-109 Initial FDA Decision on Emergency Contraceptive
and we have revised the report to more clearly describe the reasons for 

our finding.

Within FDA, CDER oversees the switch of drugs from prescription to OTC. 

Generally, prescription drugs are drugs that are safe for use only under the 

supervision of a health care practitioner. Approved prescription drugs that 

no longer require such supervision may be marketed OTC.14 In applying

this standard, FDA will authorize a prescription-to-OTC switch only after it 

is determined that the drug in question has met the following FDA criteria: 

(1) it has an acceptable safety profile based on prescription use and 

experience;15 (2) it has a low potential to be abused; (3) it has an 

appropriate safety and therapeutic index;16 (4) it has a positive benefit–risk 

assessment; and (5) it is needed for a condition or illness that is selfrecognizable, self-limiting,17 and requires minimal intervention by a health 

care practitioner for treatment.18 FDA tries to determine if the OTC 

availability of a prescription drug will prevent or delay someone from 

seeking needed medical attention. 

One class of OTC drugs switched from prescription status, the nicotine 

products (such as Nicorette gum), has restricted access based on age—

they are available OTC only to persons 18 years of age or older. 

Generally, drugs considered for a prescription-to-OTC switch involving the 

same indication, strength, dose, duration of use, dosage form, patient 

population, and route of administration as the prescription drug require 

fewer new studies regarding safety and efficacy because such studies have 

already been submitted as part of the original new drug application 

Background 

Studies for Prescription-toOTC Switches 

 14See 21 U.S.C. § 353(b)(1), 21 C.F.R. § 310.200(b). 

15An appropriate safety profile means that a drug that has been on the market has proven

that it continues to be safe. 

16The safety and therapeutic index is the ratio between the toxic dose and the therapeutic

dose of a drug and is used as a measure of the relative safety of the drug for a particular

treatment. 

17A self-limiting condition or illness is one that without treatment runs a definite course 

within a limited period. 

18These criteria are from the transcript of the joint advisory committee meeting held on 

December 16, 2003, to discuss the Plan B OTC switch application. They were presented by

an FDA official at the meeting. 

Page 7 GAO-06-109 Initial FDA Decision on Emergency Contraceptive
(NDA).19 FDA also requires sponsors to address concerns related to 

consumers’ ability to self-diagnose and self-treat the condition. Thus, 

sponsors generally submit additional studies, such as an actual use study, 

which examines consumers’ ability to self-diagnose, and a label 

comprehension study, which examines how consumers interpret the 

drug’s proposed label. In addition to these actual use and label 

comprehension studies, FDA requires sponsors to submit updated safety 

information on adverse events reported for the prescription form of the 

drug. 

FDA Process for Switching 

First-in-a-Class 

Prescription Drug to OTC 

Figure 1 shows the flow of an OTC switch application of a first-in-a-class 

drug through the decision process within CDER. To begin the process for 

a prescription-to-OTC switch, the sponsor submits an efficacy supplement 

to an approved NDA.20 This sNDA is sent to the FDA Office of Drug 

Evaluation that oversaw the original NDA and usually is the office with 

relevant expertise. This Office of Drug Evaluation is generally responsible 

for reviews of the primary effectiveness data and safety results. After an 

application has been determined to be complete, a reviewer from this 

office assesses the design, general effectiveness, and safety of the product. 

If the application is determined to be incomplete, this office will issue a 

“refusal to file” letter to the sponsor, detailing the omissions or

inadequacies that led to this decision. 

 19Drugs that involve a different indication, strength, dose, duration of use, dosage form, 

patient population, or route of administration may require additional efficacy and safety 

studies. For example, the OTC switch of ibuprofen in 1984 was for a lower dose than

prescription ibuprofen and, therefore, required new studies showing the efficacy of the 

lower dose.

20An efficacy supplement may include a submission for proposed changes in the labeling of 

an approved product for a new indication, new dosage regimen, or significant alteration in 

the patient population. 

Page 8 GAO-06-109 Initial FDA Decision on Emergency Contraceptive
Figure 1: Flow of an OTC Switch Application through the Decision Process within

CDER for First-in-a-Class Drug

If there is concurrence between two 

offices on the decision, both office 

directors sign action letter

Source: FDA.

CDER Office or Director

“Approval”

Cycle action can be repeated

Decision

Flow of review process

“Approvable” “NotApprovable”

Drug changes from 

prescription to OTC status

Issue letter indicating the deficiencies

Office of Drug Evaluation 

(relevant subject matter expertise)

Office of Drug Evaluation V 

(OTC expertise)

Concurrence 

between two offices 

on appropriate 

action?

Yes No

and

If there is not concurrence between two offices 

on the decision, then the application is raised 

to the Director of the Office of New Drugs, 

who will sign action letter

CDER Director

If the CDER Director 

disagrees with 

outcome, the CDER 

Director may change 

the decision and will 

then sign the 

action letter

Sponsor

Office of New Drugs 

Review Review

Sponsor may submit 

an amendment to 

its sNDA addressing 

the deficiencies

Note: As part of their decision process, the Offices of Drug Evaluation also get input from CDER’s 

Office of Drug Safety. They also may convene a meeting of advisory committees. 

Page 9 GAO-06-109 Initial FDA Decision on Emergency Contraceptive
When an Office of Drug Evaluation with relevant expertise receives a 

fileable sNDA for an OTC drug switch, it notifies the Office of Drug 

Evaluation V and its Division of Over-the-Counter Drug Products, which 

has relevant expertise in OTC drug products. Generally, the Office of Drug 

Evaluation V oversees the review of (1) the suitability of the product for 

OTC use and (2) safety experiences during the marketing of the 

prescription product. A reviewer from this office assesses studies related 

to OTC marketing, including the actual use and label comprehension 

studies. CDER’s Office of Drug Safety conducts additional reviews of the 

label comprehension studies, reviews postmarketing safety data of the 

prescription drug, and provides reports to reviewing staff in other offices 

upon request. 

FDA can convene advisory committee meetings for prescription-to-OTC 

switch applications. Advisory committees include outside experts, such as

medical professionals and researchers, who provide FDA with 

independent advice and recommendations. Members review data 

submitted by the sponsor or presented by FDA review staff, address 

questions, and vote, either supporting or opposing a switch from 

prescription-to-OTC status. Advisory committees conduct open meetings 

and offer members of the public the opportunity to express their views. 

FDA considers the advisory committees’ recommendations in its 

deliberations. However, the agency decides whether to adopt these 

recommendations on a case-by-case basis and is not required to follow the 

committees’ recommendations. 

FDA review staff from the appropriate offices of drug evaluation review 

the data presented, interpret the findings, and make recommendations to 

the respective office directors on whether the proposed OTC switch 

should be approved. Once these reviews are completed, they are sent to 

the directors of both the office of drug evaluation with relevant expertise 

and the Office of Drug Evaluation V. If both directors agree with each 

others’ review recommendation, the directors of the relevant offices of 

drug evaluation prepare an action package21 and an appropriate action 

letter for review, concurrence, and their final signatures. If the office 

directors do not concur on the decision, the application is reviewed by the 

Office of New Drugs. The Director of CDER is not directly involved in the 

 21An action package is a compilation of (1) FDA-generated documents related to the review 

from submission to final action of an NDA or efficacy supplement from the sponsor; (2) 

documents, such as meeting minutes and pharmacology reviews, pertaining to the format 

and content of the application; and (3) labeling submitted by the sponsor. 

Page 10 GAO-06-109 Initial FDA Decision on Emergency Contraceptive
approval of all drugs, but may overrule the decisions of subordinate 

officials. 

The authority to approve an OTC switch application ultimately rests with 

the Secretary of Health and Human Services. This approval authority is 

delegated to the Commissioner of FDA, then to other high-level 

management officials, and eventually to other FDA officials within lower 

levels of the agency. This delegated authority allows decisions to be made

at lower levels within the agency but assumes that management agrees 

with these decisions. The FDA Commissioner and other officials within 

the Office of the Commissioner usually do not have a role in OTC switch 

decisions, but have the authority to overrule the decisions of other FDA 

officials. 

Contraceptives There are several types of contraceptive drugs and devices, including 

barrier methods, intrauterine devices, spermicides, and hormonal 

methods. Several types of hormonal methods of contraception are 

available, including birth control pills, injectable hormones, hormonal 

implants, and ECPs. FDA has approved two ECPs, Preven and Plan B, for 

use by prescription, and Plan B is the first drug in its class to go through 

the review process by FDA to determine whether it should be allowed to

be sold OTC.22 ECPs are high dose birth control pills and have been 

available by prescription since 1998, when FDA approved Preven, a

dedicated23 combined ECP containing the hormones estrogen and 

progestin.24 Prior to 1998, many physicians instructed patients to take 

 22In 1997, a notice in the Federal Register stated that the Commissioner of FDA had 

concluded that certain combined oral contraceptives containing ethinyl estradiol and 

norgestrel or levonorgestrel are safe and effective for use as emergency contraception, and 

requested submission of NDAs for this use. See Prescription Drug Products; Certain

Combined Oral Contraceptives for Use as Postcoital Emergency Contraception, 62 Fed. 

Reg. 8610 (1997). In 2004, the manufacturer stopped production of Preven. 

23A dedicated ECP is a drug expressly meant for use as an ECP; levonorgestrel is a 

synthetic progestin commonly used in birth control pills.

24Estrogen is a hormone that is responsible for cyclic changes in the vagina and uterus.

Progestin is a hormone that prepares the endometrium for implantation of the fertilized 

egg. These hormones in oral birth control pills suppress ovulation. 

Page 11 GAO-06-109 Initial FDA Decision on Emergency Contraceptive
higher doses of oral contraceptive pills for emergency contraception, an 

“off-label” use.25

Emergency Contraceptive 

Plan B 

Plan B is a dedicated ECP containing only levonorgestrel, a type of 

progestin. The Plan B regimen is a two-pill dose of levonorgestrel (0.75 mg 

each) that is most effective when the first pill is taken as soon as possible, 

but no later than 72 hours, after contraceptive failure or unprotected 

intercourse. The second pill is taken 12 hours after the first pill. Research 

suggests that a levonorgestrel-only hormone regimen, such as Plan B, can 

reduce the risk of pregnancy by 89 percent if taken within the 72-hour 

window.26 The time constraint for maximum effectiveness associated with

Plan B has led many in the medical community and some reproductive 

health advocates to support switching Plan B to OTC, making it more 

readily available when needed. In addition, levonorgestrel-only regimens, 

such as Plan B, have fewer side effects than the combined ECP, reducing 

the incidence of two common side effects, nausea and vomiting, by 50 

percent and 70 percent, respectively.

Research has shown that levonorgestrel-only hormonal emergency 

contraception, such as Plan B,27 interferes with prefertilization events. It 

reduces the number of sperm cells in the uterine cavity, immobilizes 

sperm, and impedes further passage of sperm cells into the uterine cavity.

In addition, levonorgestrel has the capacity to delay or prevent ovulation 

from occurring.28

 25Off-label drug use occurs when physicians prescribe a drug for clinical indications other 

than those listed on the label. 

26World Health Organization, “Randomized Controlled Trial of Levonorgestrel Versus the 

Yuzpe Regimen of Combined Oral Contraceptives for Emergency Contraception,” The 

Lancet, vol. 352 (1998): 428-433. 

27Horacio B. Croxatto and others, “Mechanism of Action of Hormonal Preparations Used 

for Emergency Contraception: A Review of the Literature,” Contraception, vol. 63 (2001): 

111-121; and H.B. Croxatto and others, “Pituitary-Ovarian Function Following the Standard 

Levonorgestrel Emergency Contraceptive Dose or a Single 0.75-mg Dose Given on the Days

Preceding Ovulation,” Contraception, vol. 70 (2004): 442-450.

28Ovulation occurs when a mature egg is released from the ovary, is pushed down the 

fallopian tube, and is available to be fertilized.

Page 12 GAO-06-109 Initial FDA Decision on Emergency Contraceptive
ECPs have not been shown to cause a postfertilization event—a change in

the uterus that could interfere with implantation of a fertilized egg.29 Some 

researchers argue that an interference with the implantation of a fertilized 

egg is unlikely to happen because progestins, whether natural or synthetic,

help to sustain pregnancy.

30 In addition, there is no evidence that one burst

of levonorgestrel without estrogen can prevent implantation. However, 

researchers have concluded that the possibility of a postfertilization event 

cannot be ruled out, noting that it would be unethical and logistically 

difficult to conduct the necessary research.31 ECPs, including Plan B, do 

not interfere with an established pregnancy. 

On May 6, 2004, the Acting Director of CDER rejected the 

recommendations of a joint advisory committee and FDA review officials 

and signed the not-approvable letter for the Plan B OTC switch 

application. Four aspects of FDA’s review process were unusual: officials 

who would normally have been responsible for signing an action letter 

disagreed with the decision and did not sign the not-approvable letter for 

Plan B; high-level management was more involved than for other OTC 

switch applications; conflicting accounts exist of whether the decision to 

not approve the application was made before the reviews were completed;

and the rationale for the not-approvable decision was novel and did not 

follow FDA’s traditional practices. 

On May 6, 2004, the Acting Director of CDER rejected the 

recommendations of a joint advisory committee and FDA review officials 

by signing the not-approvable letter for the Plan B OTC switch application.

This action concluded a review process that began on April 16, 2003, when 

WCC submitted a standard sNDA requesting that Plan B be made available 

without a prescription. In the OTC switch application, the proposed OTC 

Aspects of FDA’s 

Review of the Plan B 

Switch Application 

Were Unusual 

The Acting Director of 

CDER Rejected the 

Recommendations of a 

Joint Advisory Committee 

and FDA’s Review Officials 

 29Implantation is the embedding of the fertilized egg in the uterus six or seven days after 

fertilization. See A.L. Muller and others, “Postcoital Treatment with Levonorgestrel Does 

Not Disrupt Postfertilization Events in the Rat,” Contraception, vol. 67 (2003): 415-419. 

30Horacio B. Croxatto, Maria E. Ortiz, and Andres L. Muller, “Mechanisms of Action of

Emergency Contraception,” Steroids, vol. 68 (2003):1095-1098. 

31It has not been possible to identify groups of women who had taken ECPs after 

fertilization so as to assess their effect on the establishment of a pregnancy. Therefore, 

there is no direct evidence, either for or against, the hypothesis that ECPs prevent 

pregnancy by affecting postfertilization events. See Croxatto, Ortiz, and Muller, 

“Mechanisms of Action of Emergency Contraception,” 1096.

Page 13 GAO-06-109 Initial FDA Decision on Emergency Contraceptive
dose and administration schedule were identical to that for Plan B’s 

prescription use. The application also included an actual use study and a 

label comprehension study to assess potential users’ understanding of how 

to administer the product. 

Following FDA’s procedures for a review of an OTC switch application, 

the sNDA was submitted to the Office of Drug Evaluation III—which 

includes the Division of Reproductive and Urologic Drug Products, whose 

staff also reviewed the prescription Plan B application. Table 1 includes a 

brief timeline of events involving Plan B and the initial OTC switch 

application. (See app. III for a more detailed timeline.) On June 9, 2003, 

review staff within the Office of Drug Evaluation III determined the Plan B 

sNDA to be fileable and accepted it for review. The sNDA was then 

submitted to the Office of Drug Evaluation V—which includes the Division 

of Over-the-Counter Drug Products, whose staff have expertise with OTC 

drugs—for concurrent review, also in accordance with FDA’s review 

procedures. FDA also convened a joint public meeting of two of its 

advisory committees—the NDAC and the ACRHD—during which the 

committees’ members reviewed documentation and voted on answers to 

specific questions asked by FDA review staff from both offices, including 

whether Plan B should be granted OTC marketing status. On December 16, 

2003, the members of the joint advisory committee voted 23 to 4 to 

recommend approving a switch in Plan B’s marketing status from 

prescription to OTC.32 Members of the joint advisory committee also voted

on other aspects of the Plan B application. For example, members voted 

27 to 1 that Plan B could be appropriately used as recommended by the 

label and that the actual use data were generalizable to the overall 

population, including adolescents. 

 32For this particular vote, 12 out of 13 members on the NDAC voted in favor of the 

proposed OTC switch for Plan B and 11 out of 15 members on the ACRHD also supported

the switch (the final vote was 23 to 4 because 1 of the committee members of the ACRHD 

left before the vote). In addition, 1 advisory committee member submitted a letter to FDA, 

outlining why Plan B should not be approved for OTC use. Media reports have suggested

that this letter was requested by someone within FDA. In its technical comments on a draft

of this report, FDA stated that this letter was not solicited by the agency and noted that the 

letter itself does not represent that the agency requested the letter. We found that all of the

points raised in the letter were already part of the public record because they had been

discussed at the advisory committee meeting. 

Page 14 GAO-06-109 Initial FDA Decision on Emergency Contraceptive
Table 1: Brief Timeline of Major Plan B Events Related to the Initial OTC Switch Application 

Date Event

July 28, 1999 FDA approved Plan B as a prescription form of emergency contraception. 

April 18, 2002 Review staff within the Office of Drug Evaluation III denied WCC’s proposal that FDA request that it 

conduct two pediatric studies—a pharmacokinetic study and a safety study—on the use of prescription 

Plan B in subjects as young as 12 years of age in exchange for extending the drug’s market exclusivity for 

6 months, as permitted under the Federal Food, Drug, and Cosmetic Act.a 

June 5, 2002 A briefing for the Office of the Commissioner was held to discuss the expected application to switch Plan B 

to OTC. Meeting attendees included the Deputy Commissioner,b

 the agency’s Chief Counsel, the thenDirector of CDER, the Director of the Office of New Drugs, and review staff within the Offices of Drug 

Evaluation III and V. 

September 23, 2002 FDA officials within the Office of New Drugs and the Offices of Drug Evaluation III and V and the sponsor 

held a meeting during which FDA officials provided guidance on the OTC switch application, which was to 

be submitted. According to meeting minutes, FDA officials and the sponsor discussed behavioral issues in

adolescents and the possibility of a behind-the-counter option or a possible age restriction.

c

 

April 16, 2003 WCC submitted an sNDA to FDA to allow Plan B to be sold OTC. 

June 9, 2003 FDA set a Prescription Drug User Fee Act (PDUFA) goal date of February 22, 2004, to reach a decision on 

the application.d

December 16, 2003 At a joint meeting of the NDAC and the ACRHD, members voted 23 to 4 to recommend approving the 

switch of Plan B from prescription to OTC. 

January 15, 2004 A meeting was held during which the Acting Director of CDER informed review staff within the Offices of 

Drug Evaluation III and V that a not-approvable decision was “recommended” by the Office of the 

Commissioner. Minutes from this meeting also noted that attendees agreed that review staff would 

complete their reviews and collect additional data to be presented to the Commissioner and the Acting 

Director of CDER some time in February. 

Review staff within the Offices of Drug Evaluation III and V later noted in their completed reviews of the 

Plan B application that they were told at this meeting that the decision on the Plan B application would be

made at a level higher than the Offices of Drug Evaluation. 

January 21, 2004 A memorandum from the Director of the Office of Drug Evaluation V concluded that adequate data had

been submitted to approve Plan B for OTC marketing. 

January 23, 2004 A meeting was held between FDA officials within the Office of New Drugs and the Offices of Drug 

Evaluation III and V and Barr Pharmaceuticals, Inc./WCC. According to meeting minutes, FDA officials told 

the sponsor that the decision on the application would be made at a level higher than the Offices of Drug 

Evaluation. The Director of the Office of New Drugs told the sponsor that such a high-level decision was

not typical. 

February 2, 2004 Review staff within the Office of Drug Evaluation III requested that the sponsor reanalyze the adolescent 

data of the Plan B actual use study for those under 18 years of age. 

February 13, 2004 FDA confirmed that it had extended the PDUFA goal date for a decision on the Plan B switch application 

for 90 days due to the submission of the requested reanalysis of adolescent data from the actual use study 

by the sponsor. The extended PDUFA goal date was May 21, 2004. 

February 18, 2004 A briefing was held during which review staff within the Offices of Drug Evaluation III and V presented their

analysis of additional summary data to the Commissioner on the use and behavior of adolescents in 

association with increased access to ECPs. According to meeting minutes, review staff recommended that 

Plan B have an OTC marketing status without restriction. The meeting minutes also noted that the 

Commissioner directed CDER to work with the sponsor on a marketing plan to limit the availability of Plan

B in an OTC setting and to consider the most appropriate ages that should be restricted from OTC access. 

February 26, 2004 Barr Pharmaceuticals, Inc., completed acquisition of the marketing rights of Plan B from WCC. 

Page 15 GAO-06-109 Initial FDA Decision on Emergency Contraceptive
Date Event

April 2, 2004 The Deputy Director of the Office of Drug Evaluation III completed the office’s review of the Plan B 

application in which she recommended that the product be approved for use as an emergency 

contraceptive in the OTC setting without age restriction. 

April 22, 2004 The Director of the Office of New Drugs issued his review, in which he concurred with the

recommendations of both Offices of Drug Evaluation III and V. In his review, he recommended that the 

application be approved to permit OTC availability of Plan B without age restriction. 

May 2, 2004 According to an internal FDA e-mail, the Acting Director of CDER contacted the Director of the Office of 

Pediatric Therapeutics, requesting assistance on language regarding cognitive development in 

adolescents. 

May 5, 2004 A teleconference was held during which the Acting Director of CDER informed Barr Pharmaceuticals, Inc., 

officials of the not-approvable action and asked permission to release the not-approvable letter. According 

to FDA regulations, without consent of the sponsor, the agency cannot publicly release data or information

contained in an application before an approval letter is issued.

e

May 6, 2004 FDA issued a not-approvable letter, denying Plan B OTC marketing status, citing a lack of adequate data

regarding safe use among younger adolescents. 

Source: GAO analysis of FDA data. 

a

See 21 U.S.C. § 355a(b), (c). FDA may request that manufacturers of new or already-marketed 

drugs conduct studies of their drugs in pediatric populations where it believes that such studies will 

lead to additional health benefits. Studies completed in accordance with FDA requirements entitle the 

manufacturer to an additional 6 months of marketing exclusivity. In its technical comments on the 

draft of this report, FDA stated that it did not ask for pediatric data for the prescription version of Plan 

B because the product’s physiological effects are the same in younger and older women and because 

a health care practitioner is involved in dispensing prescription drugs. 

b

On September 23, 2005, the Commissioner of FDA, who was appointed on July 18, 2005, resigned 

from his position. He held the title of Deputy Commissioner from February 24, 2002, until March 26, 

2004, when he was named Acting Commissioner. Because he was Deputy Commissioner during 

most of the time covered by this report—for those events associated with the initial Plan B switch 

application through the May 6, 2004, decision—we use the title of Deputy Commissioner for him in 

this report. 

c

Behind-the-counter is defined as a classification of drug products that do not require a prescription 

but are also unlike OTC products in that there is a measure of clinical oversight in their use. For 

behind-the-counter products, pharmacists are able to intervene by advising patients on the product’s 

proper use and associated risks and by referring them to their physicians when appropriate. See 

Robert I. Field, “Support Grows for a Third Class of ‘Behind-the-Counter’ Drugs,” Pharmacy and 

Therapeutics, vol. 30, no.5 (2005): 260-261. 

d

FDA, in collaboration with various stakeholders, including representatives from consumer, patient, 

and health care provider groups and the pharmaceutical and biotechnology industries, has developed 

performance goals for the time to complete the review of an application submitted to the agency. 

These goals have been incorporated by reference into PDUFA. 

e

See 21 C.F.R. § 314.430(d)(1). 

A meeting was held on January 15, 2004, between officials within the office 

of the CDER Director and review staff within the Offices of Drug 

Evaluation III and V about the Office of the Commissioner’s position on 

the acceptability of the Plan B OTC switch application. FDA’s minutes 

from this meeting stated that the Acting Director of CDER informed 

review staff that a not-approvable letter was “recommended” based on the 

need for more data to clearly establish appropriate use in younger 

Page 16 GAO-06-109 Initial FDA Decision on Emergency Contraceptive
adolescents.33 Meeting minutes also stated that the Acting Director of 

CDER raised multiple issues, including the “very limited data” on younger

adolescents in the actual use and label comprehension studies and 

concerns about younger adolescents’ ability to appropriately use Plan B 

without a learned intermediary, such as a physician.34 The minutes also 

noted that the Acting Director of CDER raised possible options to address 

these concerns, including asking the sponsor to collect more data to show

appropriate use by those 18 years of age and under or by limiting the 

availability of the product by, for example, restricting distribution to 

minors or restricting pharmacy access to a behind-the-counter option.35

According to review staff within the Offices of Drug Evaluation III and V 

who we spoke with and as documented in their respective reviews, at this

January 2004 meeting the Acting Director of CDER also told them that the 

decision on the Plan B OTC switch application would be made at a “level 

higher than them [the Offices of Drug Evaluation].”

36

At this January 2004, meeting, review staff said they also told the Acting 

Director of CDER that they had not yet completed their reviews and that 

additional data existed on the use of ECPs in younger adolescents of 

which high-level management might not be aware. According to meeting 

minutes, it was agreed that review staff would complete their reviews as 

 33Minutes of internal FDA meetings discussed in this report were written either by a staff 

member within the Office of Drug Evaluation III or by the Executive Secretariat within the

Office of the Commissioner. For meeting minutes written by the staff member within the 

Office of Drug Evaluation III, attendees either reviewed or concurred with the minutes and 

documented this by including their names at the end of the minutes. For summaries written 

by the Executive Secretariat, there was no documentation of a review or of concurrence by 

attendees. FDA officials told us that summaries from meetings within the Office of the

Commissioner are not reviewed or concurred with by attendees. The minutes for the 

January 15, 2004, meeting were written by a staff member within the Office of Drug 

Evaluation III. 

34For this report, “younger adolescents” refers to postmenarcheal women 16 years of age

and under. 

35Behind-the-counter is defined as a classification of drug products that do not require a 

prescription but are also unlike OTC products in that there is a measure of clinical 

oversight in their use. For behind-the-counter products, pharmacists are able to intervene

by advising patients on the product’s proper use and associated risks and by referring them

to their physicians when appropriate. See Field, “Support Grows for a Third Class of 

‘Behind-the-Counter’ Drugs,” 260. 

36According to FDA officials we spoke with and FDA’s manuals of policies and procedures

we reviewed, because Plan B is a first-in-the-class drug, authority for deciding the action on

the application would normally be delegated to the directors of the reviewing offices of 

drug evaluation. 

Page 17 GAO-06-109 Initial FDA Decision on Emergency Contraceptive
well as obtain these data and present them to the Commissioner, who had 

expressed a willingness to meet with review staff to further discuss the 

data and these concerns. Review staff told us they then requested 

additional data from the sponsor and contacted academic researchers in 

the United States as well as international researchers about ongoing 

studies examining younger adolescents and behavioral changes associated

with increased access to ECPs.37 Review staff identified five additional 

studies in which ECPs were provided in advance to study participants. 

Review staff also reevaluated data previously submitted with the Plan B 

OTC switch application.

On February 18, 2004, review staff within the Offices of Drug Evaluation III 

and V presented their findings to high-level management, including the 

Commissioner and the Acting Director of CDER. According to interviews 

with officials from the Office of New Drugs and review staff within the 

Offices of Drug Evaluation III and V, and as documented in their 

respective reviews of the Plan B application, they said these data provided

sufficient evidence that there was neither an increase in risky behaviors 

nor any difference in appropriate use between younger adolescents and 

older populations. According to FDA’s minutes of this meeting, the 

Commissioner expressed multiple points, including the potential for 

changes in future contraceptive behaviors after adolescents took Plan B 

and that counseling by a learned intermediary might be beneficial, 

particularly for adolescents.38 He also noted that he was not convinced that

the additional studies used as evidence had “enough power” to determine 

if behavioral differences existed between adults and adolescents.39

According to the minutes, the meeting ended with the conclusion that 

CDER staff would continue working with the sponsor on a “marketing 

plan to limit availability of the product over the counter and to consider 

the most appropriate age groups to be restricted from access to the 

 37When FDA requested additional adolescent-use data from the sponsor, review staff 

determined that the data submitted were sufficient to warrant a major amendment to the

sNDA. Thus, on February 13, 2004, FDA confirmed that it had extended the PDUFA goal 

date for the decision on the Plan B OTC switch application by 90 days from its original 

PDUFA goal date of February 22, 2004. The extended PDUFA goal date was May 21, 2004. 

38These meeting minutes were written by a staff member within the Office of Drug

Evaluation III. 

39Having enough power means having a sample size large enough to statistically detect 

actual differences between two groups. 

Page 18 GAO-06-109 Initial FDA Decision on Emergency Contraceptive
product.” In addition, according to meeting minutes, the Commissioner 

requested a “rapid action” on the Plan B OTC switch application.40

Four Aspects of FDA’s 

Review of the Plan B OTC 

Switch Application Were 

Unusual 

Aspects of FDA’s review of the Plan B OTC switch application were 

unusual compared to the agency’s regular review process. First, the FDA 

officials who would normally sign an action letter for an OTC switch 

application disagreed with the decision and did not sign the Plan B notapprovable letter; as a result, the Acting Director of CDER did so. Second, 

the review process for the Plan B OTC switch application was marked by a 

level of involvement by FDA high-level management that has not been 

typical for OTC switch applications. Third, conflicting accounts exist 

regarding when the decision to deny the application was made. Finally, the 

Acting Director of CDER’s rationale for denying the application was novel 

for an OTC switch decision. 

By early April 2004, the reviews from the Offices of Drug Evaluation III 

and V were completed. The directors of these offices agreed with the 

recommendations of the joint advisory committee and review staff that 

Plan B should be made available without a prescription. Nonetheless, the 

office directors told us that they were asked by high-level management to

draft a not-approvable letter. Both office directors also told us they did not 

agree with a not-approvable action and did not sign the not-approvable 

letter. 

FDA Officials Normally 

Responsible for Signing the 

Action Letter Did Not Do So 

The issue was then raised to the Office of New Drugs. The Director of the

Office of New Drugs reviewed the staff’s analysis of the application and 

 40We attempted to interview the individual who had been the Commissioner of FDA until 

March 2004. We were unable to arrange an interview, and he did not respond to written 

questions we submitted. However, he did provide a written comment to us. The former 

Commissioner noted that the initial Plan B decision was made after he left FDA and that

his interactions with the Acting Director of CDER and other FDA staff in this case were 

consistent with his usual practices. We also attempted to interview the individual who had 

been the Deputy Commissioner until March 2004, when he became the Acting 

Commissioner (we refer to him as Deputy Commissioner in this report). We were unable to

arrange an interview with him or obtain a response to our written questions prior to his 

departure from FDA in September 2005. His attorney subsequently provided a written

statement on his behalf. According to the statement: (1) the Deputy Commissioner did not

have a role in the review of the Plan B switch application; (2) the Acting Director of CDER

briefed him after he became Acting Commissioner on the Acting Director’s conclusions 

regarding Plan B, and he concurred with the Acting Director’s decision; and (3) the Deputy

Commissioner did not read the reviews of the application by the staff from the Offices of 

Drug Evaluation III and V and by the Director of the Office of New Drugs, and therefore, 

could not have any comments or concerns. 

Page 19 GAO-06-109 Initial FDA Decision on Emergency Contraceptive
concurred with the recommendations of both office directors. He also did

not sign the not-approvable letter. The Director of the Office of New Drugs 

told us that it was “very, very rare” that his office would become involved 

in the signing of an action letter. According to FDA manuals of policies 

and procedures and The CDER Handbook, the Office of New Drugs would 

review decisions from the offices of drug evaluation only if there was 

disagreement between these two reviewing offices. In the case of Plan B, 

there was no disagreement between the two reviewing offices of drug 

evaluation on the approvability of the application.

The Acting Director of CDER signed the not-approvable letter, which was 

issued on May 6, 2004. According to FDA, the Acting Director of CDER did 

not ask the Directors of the Offices of Drug Evaluation III and V or the 

Director of the Office of New Drugs to sign the not-approvable letter, nor 

was the letter presented to them for their signature, because it was known 

that they did not agree with the not-approvable action. 

High-level FDA management became more involved than usual in the 

review process for the Plan B OTC switch application. According to 

review staff within the Offices of Drug Evaluation III and V that we spoke 

with and as documented in their respective reviews, at a meeting held on

January 15, 2004, the Acting Director of CDER informed them that the 

decision for the Plan B OTC switch application would be made by highlevel management. This action removed decision-making authority from 

the directors of the reviewing offices who would normally make the 

decision. According to minutes from a subsequent meeting between 

review officials and the sponsor on January 23, 2004, the Director of the 

Office of New Drugs informed the sponsor that such a high-level decision

was not typical of CDER’s procedures for drug approvals. 

High-Level FDA Management 

Was More Involved Than Usual 

in the Review Process for the 

Plan B Prescription-to-OTC 

Switch Application 

The Acting Director of CDER told us that management needed to be 

comfortable with review staff’s final decision because of the high visibility 

and sensitivity of the Plan B OTC switch application. He and other senior 

FDA officials told us that involvement by high-level management stemmed 

from the agency’s practice of delegated authority. In addition to highly 

visible and sensitive cases, they said that the Commissioner and the 

Director of CDER would also generally become involved in cases that 

would potentially have a far-reaching impact or in cases in which 

management had a different view or disagreed with review staff. Although 

such cases are rare, FDA officials cited other examples when high-level 

Page 20 GAO-06-109 Initial FDA Decision on Emergency Contraceptive
management was more involved in the review process for a drug 

application than normal—the approval of thalidomide for the treatment of 

leprosy in 199841 and the approval of mifepristone for the termination of 

early pregnancy in 2000.42 Unlike Plan B, the examples FDA officials 

provided us did not involve OTC switch applications. 

FDA officials gave conflicting accounts of when the not-approvable 

decision for the Plan B OTC switch application was made. FDA officials, 

including the Director and Deputy Director of the Office of New Drugs and 

the Directors of the Offices of Drug Evaluation III and V, told us that they 

were told by high-level management that the Plan B OTC switch 

application would be denied months before staff had completed their 

reviews of the application. The Director and Deputy Director of the Office

of New Drugs told us that they were told by the Acting Deputy 

Commissioner for Operations43 and the Acting Director of CDER, after the 

Plan B public meeting in December 2003, that the decision on the Plan B 

application would be not-approvable. They informed us that they were 

also told that the direction for this decision came from the Office of the

Commissioner. The Acting Deputy Commissioner for Operations and the 

Acting Director of CDER denied that they had said that the application 

would not be approved. In addition, although minutes of the January 15,

2004, meeting stated that the Acting Director told review staff that a notapprovable decision was “recommended,” review staff documented that 

they were told at this meeting that the decision would be not-approvable. 

Both office reviews were not completed until April 2004. 

FDA Officials Gave Conflicting 

Accounts of When the Decision 

to Not Approve Plan B Was 

Made 

 41Leprosy is a chronic bacterial infection that primarily affects the skin, nerves, and mucus 

membranes and causes deformities of the face and extremities. For the thalidomide NDA, 

the Director of CDER at that time disagreed with review staff on whether the NDA should 

be approved. Review staff were concerned about the potential off-label use of the drug.

However, the Director disagreed and overruled review staff and approved the thalidomide

NDA. 

42For mifepristone, there was no disagreement between high-level management and the

review staff on whether the NDA should be approved. Rather, the Commissioner at that

time signed the approval letter out of concern regarding the protection of the identities of

staff that had reviewed the application. 

43The Acting Deputy Commissioner for Operations was the Director of CDER when the

initial Plan B OTC switch application was submitted in April 2003. She told us that she

became the Acting Deputy Commissioner for Operations in March 2004, and that her role in

the review of the initial Plan B OTC switch application was as a consultant to the Acting 

Director of CDER. 

Page 21 GAO-06-109 Initial FDA Decision on Emergency Contraceptive
However, the Acting Director of CDER told us that he made the decision

to not approve the Plan B OTC switch application shortly before signing 

the action letter. He also informed us that his decision was made in 

consultation with other high-level management officials, including the 

Commissioner and the Acting Deputy Commissioner for Operations, but 

that he was not directed to reach a particular decision. The Acting 

Director also told us that these high-level management officials agreed 

with his decision. When we asked the Acting Director about his meeting 

with officials from the Office of New Drugs in December 2003, he told us 

that he might have indicated to the Director and Deputy Director that the 

agency was “tending” or “thinking of going” in the direction of a notapprovable decision, but that this was not the final decision. Furthermore, 

although he told us that he was “90 percent sure” as early as January 2004,

that the decision would be not-approvable, the Acting Director told us he 

made his final decision only in the last few weeks prior to issuing the 

action letter, after he had reviewed all of the documentation associated 

with the application. 

The Acting Director of CDER told us that the rationale for his decision was 

not fully developed until a few days before the action letter was issued on 

May 6, 2004. According to internal FDA e-mails we reviewed, the Acting 

Director of CDER contacted the Director of the Office of Pediatric 

Therapeutics on May 2, 2004, requesting assistance on language regarding

cognitive development during early adolescence to support his decision. 

According to these e-mails, the Director of the Office of Pediatric 

Therapeutics responded that she would consult with another official with 

a background in developmental pediatrics and would follow up with 

“behavioral science information as to why one cannot extrapolate decision 

making on safety issues” from older to younger adolescents. 

The rationale for the Acting Director of CDER’s decision was novel and 

did not follow FDA’s traditional practices. The Acting Director was 

concerned about the potential impact that the OTC marketing of Plan B 

would have on the propensity for younger adolescents to engage in unsafe

sexual behaviors because of their lack of cognitive maturity. The Acting 

Director further concluded that because these differences in cognitive 

development made it inappropriate to extrapolate data from older to 

younger adolescents in this case, there was insufficient data on the use of

Plan B among younger adolescents. FDA review officials disagreed with 

the Acting Director’s rationale and noted that the agency had not 

considered behavioral implications resulting from differences in cognitive 

development in prior OTC switch decisions. 

The Acting Director’s Rationale 

for the Not-Approvable 

Decision Was Novel and Varied 

from FDA’s Traditional 

Practices 

Page 22 GAO-06-109 Initial FDA Decision on Emergency Contraceptive
The Acting Director’s Rationale Was Based on His Concerns about 

Risk-Taking in Younger Adolescents 

The Acting Director of CDER told us he signed the not-approvable letter

because of his concerns about the lack of cognitive development and the 

potential for risky behaviors among younger adolescents resulting from 

increased access to Plan B. For example, he noted increased access to 

Plan B could potentially result in an increase in unsafe sexual activity, 

particularly among younger adolescents—an age group, he noted, that has 

a tendency to engage in risky behaviors because of their level of cognitive

development. This change in behavior could be represented by changes in

measurable indicators, such as a decrease in condom use or an increase in

the transmission of sexually transmitted diseases (STD).44

In his memorandum on his review of the Plan B OTC switch application, 

the Acting Director of CDER also stated that because younger adolescents’ 

cognitive maturity related to controlling impulsive behavior is less 

developed than older adolescents’, he did not consider it appropriate to 

extrapolate data from older to younger adolescents in this case. (See app. 

IV for a copy of the Acting Director of CDER’s memorandum.) He 

specifically noted the following: 

“In making decisions about pediatric use, it is often possible to extrapolate data from one 

age group to another, based on knowledge of the similarity of the condition. However, in 

this case, adolescence is known to be a time of rapid and profound physical and emotional 

change. . . . Because of these large developmental differences, I believe that it is very 

difficult to extrapolate data on behavior from older ages to younger ages. I am 

uncomfortable with our current level of knowledge about the potential differential impact

of OTC availability of Plan B on these age subsets.” 

Some other officials we spoke with supported the Acting Director’s 

concerns about extrapolating data from older to younger adolescents. For 

example, the Director of the Office of Pediatric Therapeutics told us and 

 44For the actual use study for the Plan B OTC switch application, an additional observation 

was included along with the two study objectives. This observation involved collecting and 

comparing data from study participants on the use of emergency and regular 

contraception, such as a change in condom use. These data were collected at the time 

participants enrolled in the study and compared to data collected during a follow-up, 4

weeks later. However, although these data were considered relevant to the application by 

the sponsor and FDA officials, the sponsor noted that the actual use study was not 

primarily designed for assessing the potential risk behaviors of potential users of Plan B in

an OTC setting. 

Page 23 GAO-06-109 Initial FDA Decision on Emergency Contraceptive
noted in e-mails to the Acting Director of CDER, which we reviewed, that

the difference in cognitive development and maturity between older and 

younger adolescents and the potential impact this would have on 

behaviors warranted a separate analysis of this latter age group. In 

addition, one of the members of the joint advisory committee we spoke 

with said he was also concerned about extrapolating data from older to 

younger age groups because he perceived weaknesses in the actual use 

and label comprehension studies submitted by the sponsor.45

Because of these concerns, the Acting Director concluded that the Plan B 

OTC switch application needed more data specific to younger adolescents. 

In the not-approvable letter, the Acting Director stated there were too few 

younger adolescents in the sponsor’s actual use study to support the Plan 

B OTC switch application. Specifically, he highlighted that only 29 of 585 

participants in the study were 14 years to 16 years of age and none were 

under 14 years of age. Although he acknowledged concerns about the 

difficulty of including younger adolescents in actual use studies, he told us

that it was not impossible to enroll younger adolescents in studies, noting 

that studies for other products have been conducted involving younger 

participants, including those as young as infants. Some of the Acting 

Director’s concerns regarding the low number of younger adolescents 

were also raised by other review staff and members of the joint advisory 

committee. For example, one FDA reviewer who recommended an 

approvable action on the Plan B OTC switch application noted that despite 

a reanalysis of the actual use study data of subjects aged 14 years to 17 

years, the sample size was too small and “significantly limit[ed] 

assessment of potential risky/unsafe sexual behavior associated with OTC 

accessibility of Plan B.” 

Although review staff within the Offices of Drug Evaluation III and V 

presented him with additional data on sexual behaviors of younger 

adolescents in association with increased access to ECPs, the Acting 

Director of CDER determined that these data were not adequate to 

support the approval of Plan B for OTC use. He provided his reasoning in 

 45This committee member told us he was specifically concerned that the actual use study

was largely conducted in family planning clinics, saying this could bias the results of the 

study by potentially introducing study participants to health care professionals who could 

educate them on the use of ECPs. For the label comprehension study, he was concerned 

about the poor results among lower-educated participants. This committee member told us

that literacy and age were a concern because younger age groups are by definition 

considered among the lower educated. 

Page 24 GAO-06-109 Initial FDA Decision on Emergency Contraceptive
his memorandum, stating that these studies were either “not conducted in

the general population or they provide[d] product education assistance 

beyond what adolescents would receive in an OTC situation, where no 

contact with a health care professional is expected.” 

The Acting Director of CDER’s rationale varied from FDA’s traditional 

practices by considering the potential implications OTC access of Plan B 

would have on the sexual behavior of younger adolescents based on their 

lack of cognitive maturity and by not accepting the validity of

extrapolating data from older to younger adolescents. Although he 

acknowledged to us that considering adolescents’ cognitive development 

as a rationale for a not-approvable decision was unprecedented, the Acting

Director also told us that FDA had recently increased its focus on pediatric 

issues. He noted that pediatric issues were currently being raised in 

prescription drug reviews and believed the same should occur in OTC drug

reviews. 

FDA Review Officials Disagreed with the Acting Director’s 

Rationale for the Not-Approvable Decision 

FDA review staff, the Directors of the Offices of Drug Evaluation III and V, 

and the Director of the Office of New Drugs disagreed with the Acting 

Director of CDER’s rationale for not approving the Plan B OTC switch 

application. FDA review officials, including those from the Office of New 

Drugs, noted that traditionally FDA has not considered whether younger 

adolescents would use an OTC product differently than older adolescents, 

and the Director of the Office of New Drugs told us that it was “atypical” 

to raise the question of maturity during a drug review. These officials also

noted that FDA does not attempt to determine how a patient arrived at the 

need for a drug. Rather, drug evaluations usually begin with the need for a 

potential treatment already existing.

Review staff we spoke with acknowledged that certain behavioral 

concerns and unintended consequences are examined for an OTC switch 

application, such as whether making a drug OTC would delay a person 

from seeking medical treatment or if the drug would potentially be abused 

if it were more readily available. They told us that these issues are usually 

examined during a benefit–risk review, which is an analysis of potential 

medical outcomes. Review staff told us they examined benefit–risk issues 

for Plan B, and they concluded that concerns regarding the potential for

Page 25 GAO-06-109 Initial FDA Decision on Emergency Contraceptive
unsafe sexual behaviors among adolescents could not be supported.46 In 

addition, the review of the label comprehension study from the Office of 

Drug Safety noted that potential users of the product would be able to

appropriately use it if the sponsor made its suggested changes to the 

proposed labeling.47 Also, at the public meeting, members of the joint 

advisory committee voted 27 to 1 that the actual use study demonstrated 

that consumers could properly use Plan B as recommended by the label. 

The members of the joint advisory committee also voted 28 to 0 that the 

literature review of Plan B included in the actual use study did not show 

that Plan B would be used as a regular form of contraception. 

Furthermore, the review of the application from the Office of Drug 

Evaluation III, which included the benefit–risk assessment for Plan B, 

noted that having Plan B in an OTC setting would “pose little risk” to the 

potential user and that the risk of an adverse pregnancy outcome, such as

lower birth weight babies and premature delivery, is much higher among 

younger adolescents. The review concluded that OTC access to Plan B in 

helping younger adolescents avoid unintended pregnancies would be “of 

particular value given the greater risk of an adverse pregnancy outcome in 

this high risk group.” This review also noted that even for a large dose of 

the hormone used in Plan B, the “margin of safety appear[ed] to be high.” 

In an attempt to further address the Commissioner’s and Acting Director’s 

concerns about the potential for increased risky behavior by younger 

adolescents resulting from increased access to Plan B, review staff 

requested additional data from the sponsor and reviewed ongoing studies 

examining these concerns. FDA’s reviewers concluded that increased 

access to ECPs did not result in (1) inappropriate use by adolescents as a

substitute form of contraception, (2) an increase in the number of sexual 

partners or the frequency of unprotected intercourse, or (3) an increase in

the frequency of STDs. 

 46Only one of the review staff for the Plan B OTC switch application raised concerns 

regarding behaviors of younger adolescents. Recommending an approvable decision, he

concluded in his written review of the application that (1) the actual use study had 

insufficient data on whether OTC accessibility of Plan B might be associated with risky (or 

unsafe) sexual behaviors over the long term, particularly among adolescents; (2) the

behavioral literature did not provide strong evidence to address the inadequacies in the 

actual use study in assessing risky sexual behaviors in the target OTC populations; and (3) 

some behavioral studies in the literature suggested that providing ECPs in advance could 

encourage unsafe sexual behaviors in the study populations. 

47The changes proposed by the Office of Drug Safety were included as attachments to the 

office’s review of the label comprehension study. 

Page 26 GAO-06-109 Initial FDA Decision on Emergency Contraceptive
To reach these conclusions, review staff examined the five studies that 

provided supplies of ECPs in advance to study participants to assess the 

behavioral impact of OTC access. In one study, which included 2,090 

women aged 15 years to 24 years, there was a decrease in unprotected sex

among all age groups and no increase in the incidence of STDs compared 

to the baseline. Another study of 160 adolescent mothers included 

participants aged 14 years to 20 years. Although there were limited data 

available, this study concluded that there was no increase in unprotected 

intercourse and no decrease in condom use among participants. A third 

study of 301 adolescent women, aged 15 years to 20 years, showed similar 

results, with no increase in unprotected intercourse or STDs and no 

decrease in condom use. 

FDA officials, including those from the Office of New Drugs, also 

disagreed with the Acting Director’s determination that extrapolating data 

from older populations to younger adolescents was inappropriate. In their 

reviews, officials noted that data they reviewed showed that younger 

adolescents had outcomes similar to those of older populations. For 

example, the actual use study found that 82 percent of participants 16 

years of age or under correctly took the second dose 12 hours later, 

compared to 78 percent of those 17 years and older.48 Also, review staff 

said that overall the number of participants who were younger adolescents 

was adequate to draw conclusions about potential use among the 

adolescent population. Review staff told us they encouraged the sponsor 

to not limit enrollment or exclude adolescents from the actual use study 

and felt the study included a representative population of women that 

would potentially use Plan B. Some of the members of the joint advisory 

committee we spoke with also said they considered the number of 

younger adolescents in the actual use study as adequate.

In addition, the Director of the Office of New Drugs told us that the agency 

has not requested age-specific data often and that FDA often extrapolates 

findings, including findings on behaviors, from adults to adolescents. He 

added that given the agency’s traditional processes and the data provided

 48Although there were 29 younger adolescents aged 16 years or under enrolled in the actual 

use study, only 22 used the product and provided follow-up data for this specific question.

Of the 22 study participants who used the product and provided follow-up data, 18 reported 

that they correctly took the second dose 12 hours after the first. The total number of study

participants aged 17 years or older who also used the product and provided follow-up data

was 46. Of these 46 study participants, 36 reported that they correctly took the second dose

12 hours after the first. 

Page 27 GAO-06-109 Initial FDA Decision on Emergency Contraceptive
in the Plan B OTC switch application, there was no reason to consider the 

extrapolations done in the staff’s reviews as inappropriate. 

Based on the reviews conducted by review staff and on the 

recommendations of the joint advisory committee, the Director of the 

Office of New Drugs concluded the following in his memorandum of his 

review of the Plan B OTC switch application, issued April 22, 2004 (a copy

of this memorandum can be found in app. V): 

“In my opinion, these studies provide adequate evidence that women of childbearing

potential can use Plan B safely, effectively, and appropriately for emergency contraception 

in the non-prescription setting. The data submitted by the sponsor in support of nonprescription use of Plan B are fully consistent with the Agency’s usual standards for 

meeting the criteria for determining that a product is appropriate for such use. . . . Such a 

conclusion is consistent with how the Agency has made determinations for other OTC

products, including other forms of contraception available without a prescription. Further,

I believe that greater access to this drug will have a significant positive impact on the

public health by reducing the number of unplanned pregnancies and the number of 

abortions.” 

In his memorandum, the Director of the Office of New Drugs also noted 

that FDA has a “long history” of extrapolating findings from older 

populations to younger adolescents. He wrote that this type of 

extrapolation from older populations to younger adolescents had been

done in clinical trials for both prescription and OTC drug approvals and 

that this practice was incorporated into the Pediatric Research Equity Act 

(PREA)—the law authorizing FDA to require pediatric studies in certain 

defined circumstances.49 According to PREA, if the disease and the effects 

of the drug are “sufficiently similar” between adult and pediatric 

populations, it can be concluded that the effectiveness can be extrapolated 

from “adequate and well-controlled studies in adults” usually in 

conjunction with supplemental studies in pediatric populations. In 

addition, PREA provides that studies may not be necessary for all 

pediatric age groups, if data from one age group can be extrapolated to 

another. 

Members of the joint advisory committee expressed similar conclusions to 

those of FDA review officials earlier at the public meeting in December 

2003. During the public meeting, committee members voted 27 to 1 that 

 49See 21 U.S.C. § 355c(a)(2)(B). 

Page 28 GAO-06-109 Initial FDA Decision on Emergency Contraceptive
the actual use study data were generalizable to the overall population of 

OTC users, including adolescents. 

The decision to not approve the Plan B OTC switch application was not 

typical of the other 67 proposed prescription-to-OTC switch decisions 

made from 1994 through 2004. The decision of the Plan B application 

stands out from these other OTC switch applications for two reasons: it 

was the only decision that was not approved after the members of the joint

advisory committee voted to recommend approval of the application, and 

the action letter was signed by the Acting Director of CDER instead of the 

directors of the offices where the application was reviewed.

From 1994 through 2004, Plan B was the only prescription-to-OTC switch 

decision that was not approved after the joint advisory committee voted to 

recommend approval of the application. FDA advisory committees 

considered 23 OTC switch applications during this period; the Plan B OTC 

switch application was the only 1 of those 23 that was not approved after

the joint advisory committee voted to recommend approval of the 

application. In addition, there has been only 1 other decision for an OTC 

switch application that did not follow the recommendations of the joint 

advisory committee. This other OTC switch application, for the drug 

Aleve, was approved for OTC status by FDA in 1994, although the joint 

advisory committee opposed the switch. The NDAC met jointly with the 

Arthritis Drugs Advisory Committee to discuss the OTC switch application 

for Aleve in June 1993 and recommended that the application not be 

approved. Following this meeting, the sponsor made changes to address 

the joint advisory committee’s concerns, and as a result of these changes, 

FDA decided to approve the application.50

Plan B Decision Was 

Not Typical of Other 

Proposed 

Prescription-to-OTC 

Switch Decisions 

Plan B Was the Only 

Prescription-to-OTC 

Switch Decision from 1994 

through 2004 That Was Not 

Approved after the Joint 

Advisory Committee Voted 

to Recommend Approval 

of the Application 

 50Reasons that the joint advisory committee gave for the recommendation against the OTC 

switch included that the dose was too high, the labeling for people over 65 years of age was 

incorrect, and no additional labeling was included for children regarding the side effect of

photosensitivity. 

Page 29 GAO-06-109 Initial FDA Decision on Emergency Contraceptive
From 1994 through 2004, 94 action letters were issued during the review 

processes for the 68 prescription-to-OTC switch applications, and only 1 

action letter—the not-approvable letter for Plan B—was signed by the 

Director, in this case the Acting Director, of CDER. Given that Plan B was 

a first-in-a-class drug, the Directors of the Offices of Drug Evaluation III 

and V would normally jointly sign the action letter. The Plan B application

was 1 of 68 proposed OTC switch applications decided by FDA from 1994 

through 2004, and 14 of those 68 applications, including the Plan B 

application, were issued not-approvable letters. Eight of those 14 

applications were eventually approved. Plan B was the only contraceptive

or emergency contraceptive proposed for an OTC switch during this 

period. Thirty-eight OTC switch applications, including Plan B, were for 

the same dose, population, and indication, and all but 3 applications were 

eventually approved. 

According to the Deputy Director of the Office of New Drugs, there are no

age-related marketing restrictions for any FDA-approved contraceptives, 

and FDA has not required any pediatric studies. Condoms and spermicides 

are available to anyone OTC, while intrauterine devices; diaphragms; 

cervical caps; and hormonal methods of contraception, including ECPs, 

are available to anyone with a prescription. For hormonal contraceptives, 

FDA has assumed that suppression of ovulation is the same in all 

postmenarcheal females, regardless of age. The Deputy Director of the 

Office of New Drugs told us that all birth control pills, including ECPs, 

contain the following class labeling: “Safety and effectiveness of [trade 

name] have been established in women of reproductive age. Safety and 

efficacy are expected to be the same for postpubertal adolescents under 

the age of 16 and for users 16 years and older. Use of this product before 

menarche is not indicated.” 

Plan B Was the Only 

Prescription-to-OTC 

Switch Decision from 1994 

through 2004 in Which the 

Action Letter Was Signed 

by the Director of CDER 

There Are No AgeRelated Restrictions 

for Safety Reasons for 

Any FDA-Approved 

Contraceptives 

FDA officials from the Office of New Drugs explained that for an OTC 

switch, the safety and effectiveness issues have already been addressed 

during the initial approval process for the drug to become a prescription 

drug. For an OTC switch application, the review process is primarily 

focused on whether the drug meets the OTC switch criteria, specifically 

whether it is safe and effective for use in self-medicating.51

 51In its technical comments on the draft of this report, FDA said that it also considers age in

the labeling of OTC drug products. For example, FDA stated that there are many OTC 

drugs that have labels with dosing instructions based on age. 

Page 30 GAO-06-109 Initial FDA Decision on Emergency Contraceptive
There were no safety issues that would require age-related restrictions that 

were identified with the original NDA for prescription Plan B. FDA 

approved this application upon determining that Plan B met the statutory 

standards of safety and effectiveness, manufacturing and controls, and 

labeling. The original NDA for Plan B for use as an emergency 

contraceptive contained an extensive safety database that included 

controlled trials and literature on over 15,000 women.52 The label for 

prescription Plan B makes no age distinctions about the pharmacological 

processes of the drug, and prescription Plan B is available to anyone with

a prescription. 

FDA reviewed a draft of this report and provided comments, which are 

reprinted in appendix VI. FDA also provided technical comments, which 

we incorporated as appropriate. 

Agency Comments 

and Our Evaluation 

In its comments, FDA disagreed with our finding that three aspects of its 

decision process for the May 2004, Plan B OTC switch application were 

unusual. First, FDA said that the involvement of high-level management in

the Plan B decision was not as unusual as the draft report found. FDA 

commented that the Director of CDER is ultimately responsible for all 

decisions made within CDER, and that the Director of CDER is regularly 

involved in regulatory decisions that are not routine, including those that 

involve controversial issues. FDA also commented that the Director of 

CDER typically discusses high-profile and controversial regulatory 

decisions with officials within the Office of the Commissioner. 

While we agree with FDA that the Director of CDER and other high-level

officials generally are more likely to become directly involved in highprofile regulatory decisions and noted that in the draft of the report, we 

found that this level of involvement is unusual for OTC switch 

applications. The other examples of high-level management involvement 

given to us by FDA officials during the course of our work involved 

decisions about the marketing of prescription drugs. Also, it was unusual 

for the Acting Director of CDER to inform FDA’s review staff that it had 

been determined that the Plan B decision would be made by high-level 

management. The Acting Director did so on January 15, 2004, before the 

review staff had completed their reviews of the application. 

 52The database included trials conducted in the United States and other countries. Women 

in the study were above the age of consent for their own countries. 

Page 31 GAO-06-109 Initial FDA Decision on Emergency Contraceptive
Second, FDA took issue with what it characterized as the tone of our 

discussion about when the decision was made to deny the Plan B OTC 

switch application. FDA commented that discussions about alternative 

regulatory actions ordinarily occur in the course of decision making within 

CDER and that it is inaccurate to conclude that a decision to deny the 

application was made several months before the not-approvable letter was 

issued. However, the draft report did not assert that a decision was 

actually made several months before the letter was issued. Rather, it 

accurately noted that FDA officials gave us conflicting accounts of when 

the not-approvable decision was made. The Director and Deputy Director 

of the Office of New Drugs and other officials told us that they were 

informed during December 2003 and January 2004 that the application 

would not be approved. The Acting Director of CDER denied this, and we 

reported that his rationale for the not-approvable decision was not fully 

developed until early May 2004. 

Third, FDA disagreed with our finding that the Acting Director’s rationale 

for denying the application was novel and did not follow FDA’s traditional 

practices. FDA commented that the Acting Director’s focus on the 

potential implications to the sexual behavior of adolescent women of 

approving the Plan B OTC switch application was appropriate and 

consistent with FDA’s treatment of other OTC switch applications. 

In response to this comment, we have revised the report to more clearly 

describe the reasons for our finding. We found that the Acting Director’s 

rationale was novel because it explicitly considered the differing levels of 

cognitive maturity of adolescents of different ages, and that because of the 

Acting Director’s views about these cognitive maturity differences, he 

concluded that it was inappropriate to extrapolate data related to risky 

sexual behavior from older to younger adolescents. In his May 6, 2004, 

memorandum, the Acting Director stated that “Because of these large 

developmental differences, I believe that it is very difficult to extrapolate

data on behavior from older to younger ages.” The Acting Director 

acknowledged that considering adolescents’ cognitive development as a 

rationale for a not-approvable decision was unprecedented for an OTC 

switch application. In addition, other FDA officials told us that the agency

had not previously considered whether younger adolescents would use a 

product differently than older adolescents. For example, the Director of 

the Office of New Drugs told us that it was “atypical” to raise the question

of maturity during a drug review and that FDA has traditionally 

extrapolated findings from older to younger adolescents. Furthermore, in 

his April 22, 2004, memorandum, the Director of the Office of New Drugs 

said that “the Agency has a long history of extrapolating findings from 

Page 32 GAO-06-109 Initial FDA Decision on Emergency Contraceptive
clinical trials in older patients to adolescents in both prescription and nonprescription approvals.”

In addition, FDA disagreed with our statement in the draft report that the 

Directors of the Offices of Drug Evaluation III and V and the Director of 

the Office of New Drugs refused to sign the not-approvable letter. We used 

the term “refused” in the draft report because, in our interviews with them, 

all three of the directors told us that they did not agree with the notapprovable decision and did not sign the action letter, and one of the 

directors told us that she had been given an opportunity to sign the letter 

and refused to do so. However, in its comments, FDA said that the 

directors were not asked to sign the action letter because it was known 

that they disagreed with the Acting Director’s decision. We have revised 

the report to reflect this. 

In its technical comments, FDA asked us to emphasize that safety 

concerns regarding OTC use of drug would not be raised for prescription 

products because of the involvement of health practitioners. The draft 

report noted that prescription drugs are drugs that are safe for use only 

under supervision of a health care practitioner and that approved 

prescription drugs that no longer require such supervision may be 

marketed OTC. 

We are sending copies of this report to the Acting Commissioner of the 

Food and Drug Administration and other interested parties. We will also 

provide copies to others upon request. In addition, the report will be 

available at no charge on GAO’s Web site at http://www.gao.gov. 

If you or your staffs have any questions about this report, please contact 

me at (202) 512-7119 or crossem@gao.gov. Contact points for our Offices 

of Congressional Relations and Public Affairs may be found on the last 

page of this report. GAO staff who made major contributions to this report 

are listed in appendix VII. 

Marcia Crosse 

Director, Health Care 

Page 33 GAO-06-109 Initial FDA Decision on Emergency Contraceptive
List of Requesters 

The Honorable Edward M. Kennedy 

Ranking Minority Member 

Committee on Health, Education, Labor, 

 and Pensions 

United States Senate 

The Honorable Carl Levin 

Ranking Minority Member 

Permanent Subcommittee on 

 Investigations 

Committee on Governmental Affairs 

United States Senate 

The Honorable John D. Dingell 

Ranking Minority Member 

Committee on Energy and Commerce 

House of Representatives 

The Honorable Henry A. Waxman 

Ranking Minority Member 

Committee on Government Reform 

House of Representatives 

The Honorable Jeff Bingaman 

The Honorable Barbara Boxer 

The Honorable Maria Cantwell 

The Honorable Hillary Rodham Clinton 

The Honorable Jon Corzine 

The Honorable Mark Dayton 

The Honorable Christopher J. Dodd 

The Honorable Richard J. Durbin 

The Honorable Tom Harkin 

The Honorable Daniel K. Inouye 

The Honorable James M. Jeffords 

The Honorable Frank R. Lautenberg 

The Honorable Barbara A. Mikulski 

The Honorable Patty Murray 

The Honorable Charles E. Schumer 

The Honorable Debbie Stabenow 

The Honorable Ron Wyden 

United States Senate 

Page 34 GAO-06-109 Initial FDA Decision on Emergency Contraceptive
The Honorable Tammy Baldwin 

The Honorable Sherrod Brown 

The Honorable Lois Capps 

The Honorable Benjamin L. Cardin

The Honorable Joseph Crowley 

The Honorable Susan A. Davis 

The Honorable Lloyd Doggett 

The Honorable Sam Farr 

The Honorable Bob Filner 

The Honorable Maurice D. Hinchey 

The Honorable Rush D. Holt 

The Honorable Michael M. Honda 

The Honorable Barbara Lee 

The Honorable Nita M. Lowey 

The Honorable Carolyn B. Maloney 

The Honorable Edward J. Markey 

The Honorable James P. Moran, Jr. 

The Honorable Jerrold Nadler 

The Honorable Eleanor Holmes Norton 

The Honorable Janice D. Schakowsky 

The Honorable Louise M. Slaughter 

The Honorable Hilda L. Solis 

The Honorable Edolphus Towns 

The Honorable Mark Udall 

The Honorable Chris Van Hollen 

The Honorable Diane E. Watson 

The Honorable Lynn C. Woolsey 

House of Representatives 

Page 35 GAO-06-109 Initial FDA Decision on Emergency Contraceptive
Appendix I: Scope and Methodology Appendix I: Scope and Methodology 

To examine how the decision was made to not approve the switch of Plan 

B from prescription to over-the-counter (OTC), we reviewed documents, 

such as the Plan B OTC switch action package related to the May 6, 2004,

decision from the Food and Drug Administration (FDA). We examined 

documents produced by FDA, including official meeting minutes and the

reviews of the Plan B OTC switch application from the Offices of Drug 

Evaluation III and V and the Office of New Drugs, related to the review of

the Plan B OTC switch application. FDA officials told us that 

documentation was not available concerning some communications within 

FDA. It was not possible to determine whether such communications may 

have concerned the Plan B OTC switch application. However, we acquired

sufficient information from other FDA documents and our interviews with 

FDA officials to fully address our objectives. 

We interviewed FDA officials involved in the Plan B OTC switch 

application review, including officials from the Office of Drug Evaluation 

III, Office of Drug Evaluation V, Office of New Drugs, and Office of Drug 

Safety. We also interviewed the Acting Director of the Center for Drug 

Evaluation and Research (CDER), the Acting Deputy Commissioner for 

Operations, and the Director of the Office of Women’s Health. We 

interviewed members of FDA’s advisory committees that met jointly to 

discuss the Plan B OTC switch application—the Nonprescription Drugs 

Advisory Committee (NDAC) and the Advisory Committee for 

Reproductive Health Drugs (ACRHD)—and reviewed the transcripts of the 

meeting. In addition, we interviewed officials from Barr Pharmaceuticals,

Inc., the company currently sponsoring the Plan B application for the 

prescription-to-OTC switch, and Women’s Capital Corporation (WCC), the 

original sponsor of the Plan B OTC switch application. 

To examine how the Plan B decision compares to the decisions for other 

proposed prescription-to-OTC switches made from 1994 through 2004, we

examined the recommendations of the joint advisory committee and if 

they were followed for Plan B and the proposed OTC switch drugs that 

were decided from 1994 through 2004. We reviewed action letters and 

interviewed FDA officials and review staff as well as other outside experts 

involved with the Plan B OTC switch application. We also interviewed 

officials from the Consumer Healthcare Products Association (the 

association representing OTC drug manufacturers) about the prescriptionto-OTC switch process. 

To determine if there were age-related marketing restrictions for 

prescription Plan B and other prescription and OTC contraceptives, we 

reviewed FDA documents and interviewed FDA officials and review staff 

Page 36 GAO-06-109 Initial FDA Decision on Emergency Contraceptive
Appendix I: Scope and Methodology 

regarding safety concerns for prescription Plan B and the safety concerns 

for other prescription and OTC contraceptives. We also interviewed 

representatives from the American College of Obstetricians and 

Gynecologists, the American Academy of Pediatrics, Concerned Women 

for America, and the Planned Parenthood Federation of America, Inc., 

regarding safety concerns for Plan B and other contraceptives. 

When the source of evidence we cited is from an interview, we identified

the respondent’s title and FDA office. Whenever possible, we reviewed 

documents to verify testimonial evidence from FDA officials. When this 

was not possible, we attempted to corroborate testimonial evidence by 

interviewing multiple people about the information we obtained. In 

situations where there was no concurrence among the interviewees, we 

presented all the information provided. 

Minutes of the internal FDA meetings discussed in this report were written 

either by a staff member within the Office of Drug Evaluation III or by the 

Executive Secretariat within the Office of the Commissioner. For meeting 

minutes written by the office staff member, attendees either reviewed or 

concurred with the minutes and documented this by including their names 

at the end of the minutes. For summaries written by the Executive 

Secretariat, there was no documentation of a review or of concurrence by 

attendees included with these summaries. FDA officials told us that 

summaries from meetings within the Office of the Commissioner were not 

reviewed or concurred with by attendees. 

To verify data we received from FDA regarding proposed prescription-toOTC switch decisions made from 1994 through 2004 and the outcomes of 

advisory committee meetings for these drugs, we compared FDA’s data 

with prescription-to-OTC switch data obtained from the Consumer 

Healthcare Products Association on OTC drug switches. 

Our work examined only events and communications within FDA and 

between FDA and the Plan B sponsors; we did not consider any 

communications that may have occurred between FDA officials and other 

executive agencies. Our work examined only FDA’s actions prior to the 

May 6, 2004, not-approvable letter, and we did not examine any aspects of 

FDA’s subsequent deliberations about Plan B. We conducted our work 

from September 2004 through November 2005 in accordance with 

generally accepted government auditing standards. 

Page 37 GAO-06-109 Initial FDA Decision on Emergency Contraceptive
Appendix II: Not-Approvable Letter for the 

Prescription-to-OTC Switch Application of Appendix II: Not-Approvable Letter for the Plan B, May 6, 2004 

Prescription-to-OTC Switch Application of 

Plan B, May 6, 2004 

Page 38 GAO-06-109 Initial FDA Decision on Emergency Contraceptive
Appendix II: Not-Approvable Letter for the 

Prescription-to-OTC Switch Application of 

Plan B, May 6, 2004 

Page 39 GAO-06-109 Initial FDA Decision on Emergency Contraceptive
Appendix II: Not-Approvable Letter for the 

Prescription-to-OTC Switch Application of 

Plan B, May 6, 2004 

Page 40 GAO-06-109 Initial FDA Decision on Emergency Contraceptive
Appendix II: Not-Approvable Letter for the 

Prescription-to-OTC Switch Application of 

Plan B, May 6, 2004 

Page 41 GAO-06-109 Initial FDA Decision on Emergency Contraceptive
Appendix III: Timeline of Major Plan B 

Events Related to the Initial OTC Switch

Application 

Date Event

February 25, 1997 A notice in the Federal Register stated that the FDA Commissioner had concluded that certain 

combined oral contraceptives are safe and effective for use as emergency contraception and 

requested submission of a new drug application (NDA) for this use. 

July 28, 1999 FDA approved Plan B as a prescription form of emergency contraception. 

February 14, 2001 A citizens’ petition for direct over-the-counter (OTC) access to Plan B was filed, requesting that 

FDA grant Plan B OTC status. 

April 18, 2002 FDA review staff within the Office of Drug Evaluation III sent Women’s Capital Corporation (WCC) 

a letter, denying its proposal that FDA request that it conduct pediatric studies on the use of 

prescription Plan B as an emergency contraceptive in exchange for extending the drug’s

marketing exclusivity for 6 months, as permitted under the Federal Food, Drug, and Cosmetic Act.a

According to the letter to WCC and a memorandum by review staff within the Office of Drug 

Evaluation III, the proposed studies would have included a pharmacokinetic study and a safety 

study and would have used Plan B as an emergency contraceptive in subjects as young as 12 

years of age. According to review staff within the Office of Drug Evaluation III, once a young 

female reached menarche, she was considered an adult for contraceptives and the condition for 

using an emergency contraceptive is not unique to the pediatric population. The letter concluded 

that trials could be conducted in the adult population and then extrapolated to the pediatric

population. 

May 28, 2002 A Center Director Informational Briefing was held in response to the citizens’ petition, filed on 

February 14, 2001. Meeting attendees included the Center for Drug Evaluation and Research 

(CDER) Director and Deputy Director, the Director of Office of New Drugs, and review staff from 

the Offices of Drug Evaluation III and V. 

June 5, 2002 A briefing for the Office of the Commissioner was held to discuss the expected application to 

switch Plan B to OTC. Attendees included the Deputy Commissioner,b

 the agency’s Chief

Counsel, the then Director of CDER, the Director of the Office of New Drugs, and review staff from 

the Offices of Drug Evaluation III and V. According to the executive summary of the briefing, 

issues discussed included (1) the political sensitivity of the application, (2) consumer 

understanding of the proposed nonprescription product label, (3) the results of actual use studies 

to adequately address safety issues, (4) the review status of the supplemental new drug 

application (sNDA) upon submission, and (5) regulatory issues. 

July 10, 2002 The Director of CDER provided the Deputy Commissioner and FDA’s Chief Counsel with materials 

on the safety of emergency contraception and its mechanism of action, which were requested at 

the June 5, 2002, briefing. 

September 23, 2002 FDA officials within the Office of New Drugs and the Offices of Drug Evaluation III and V and the 

sponsor held a meeting in which FDA provided guidance on the Plan B OTC switch application, 

which was to be submitted. According to meeting minutes, agency officials and the sponsor 

discussed behavioral issues in adolescents and the possibility of a behind-the-counter option or a 

possible age restriction.c

 

April 16, 2003 WCC submitted an sNDA to FDA to allow Plan B to be sold OTC. 

June 9, 2003 FDA review staff from the Office of Drug Evaluation III determined that the sNDA was fileable and 

accepted it for review. FDA set a Prescription Drug User Fee Act (PDUFA) goal date of February 

22, 2004, to reach a decision on the application.d

Appendix III: Timeline of Major Plan B 

Events Related to the Initial OTC Switch 

Application 

Page 42 GAO-06-109 Initial FDA Decision on Emergency Contraceptive
Appendix III: Timeline of Major Plan B 

Events Related to the Initial OTC Switch

Application 

Date Event

August 22, 2003 A teleconference was held between review staff within Offices of Drug Evaluation III and V and the 

sponsor. According to minutes of this teleconference, review staff began working with the sponsor 

to prepare for the meeting of the joint advisory committee in December. Minutes also noted that 

FDA review staff suggested that the sponsor plan to address issues of age, literacy, or label 

comprehension regarding the administration of Plan B. 

September 11, 2003 Review within the Office of Drug Evaluation V requested additional information on the label 

comprehension study results from WCC. According to the official request, review staff asked for 

information including results for each question asked in the label comprehension study based on 

literacy levels; details on what criteria were used to determine if a communication objective was 

met; and other specific points of clarification on how responses were scored. 

September 26, 2003 A teleconference was held in which review staff within the Offices of Drug Evaluation III and V 

discussed the upcoming December 16, 2003, public meeting of its two advisory committees with 

WCC. According to teleconference minutes, review staff requested additional information on the 

labels used for the label comprehension and the actual use studies and on the label proposed for 

approval in the sNDA. Minutes also noted that WCC informed FDA that on September 23, 2003, a 

majority of its board voted to sell the marketing rights of Plan B to Barr Pharmaceuticals, Inc. 

October 2003 Barr Pharmaceuticals, Inc., was finalizing the purchase of the marketing rights for Plan B from 

WCC and began to act as the agent for WCC for Plan B. 

October 9, 2003 At the request of Barr Pharmaceuticals, Inc., a teleconference was held to discuss the upcoming 

joint public meeting of FDA’s advisory committees. Meeting participants from FDA included review 

staff within the Offices of Drug Evaluation III and V. According to teleconference minutes, review 

staff asked Barr Pharmaceuticals, Inc., about possible age restrictions for use of Plan B. Minutes 

also noted that Barr Pharmaceuticals, Inc., said that it intended to offer its product to women as 

young as 15 years of age. Also, Barr Pharmaceuticals, Inc., agreed to explore and report back to 

FDA on behind-the-counter marketing and the implementation of age limitations on the sale of 

Plan B. 

November 5, 2003 A reviewer within the Office of Drug Safety completed her review of the Plan B label 

comprehension study, which was initially submitted to review staff within the Office of Drug 

Evaluation III. According to the official memorandum on the review of the label comprehension 

study, the reviewer concluded that making the proposed changes to the Plan B label would likely 

result in acceptable levels of comprehension. Review staff within the Office of Drug Evaluation V 

told GAO they concurred with the reviewer’s findings. 

December 2, 2003 A meeting was held between FDA officials within the Office of New Drugs and the Offices of Drug 

Evaluation III and V and the sponsor. According to meeting minutes, FDA officials informed Barr 

Pharmaceuticals, Inc., that the agency may not be able to present a clear regulatory path for 

alternate OTC distribution mechanisms for Plan B in time for the December 16, 2003, public 

meeting. 

December 10, 2003 A briefing for the Office of the Commissioner was held to discuss the upcoming public meeting of 

the Nonprescription Drugs Advisory Committee (NDAC) and Advisory Committee for Reproductive 

Health Drugs (ACRHD). FDA participants included the Commissioner, the Acting Director of 

CDER, the Director and Deputy Director of the Office of New Drugs, and review staff within the 

Office of Drug Safety and the Offices of Drug Evaluation III and V. According to the executive 

summary of the briefing, issues discussed included the sponsor’s marketing and distribution plan 

and the effect making Plan B available OTC might have on consumers’ behavior. 

December 16, 2003 At a joint meeting of the NDAC and the ACRHD, members voted 23 to 4 to recommend approving 

the switch of Plan B from prescription to OTC. 

Page 43 GAO-06-109 Initial FDA Decision on Emergency Contraceptive
Appendix III: Timeline of Major Plan B 

Events Related to the Initial OTC Switch

Application 

Date Event

December 2003/January 2004 The Director and the Deputy Director of the Office of New Drugs told GAO they were told by the 

Acting Deputy Commissioner for Operationse

 and the Acting Director of CDER that the Plan B 

application could not be approved. These officials said they were told that this direction came from 

the Office of the Commissioner. The Acting Deputy Commissioner for Operations and the Acting 

Director of CDER told GAO they did not say this. 

January 15, 2004 A meeting was held between officials within the Office of the CDER Director and review staff 

within the Offices of Drug Evaluation III and V about the Office of the Commissioner’s position on 

the acceptability of the Plan B OTC switch application. According to meeting minutes, the Acting 

Director of CDER said that a not-approvable decision was recommended by the Office of the 

Commissioner based on the need for more data to more clearly establish appropriate use in 

younger adolescents, the need to develop a restricted distribution plan, or both. Meeting minutes 

also indicated that review staff also informed the Acting Director that their reviews were not yet 

completed and that there were additional data regarding adolescent use of Plan B. It was then 

agreed that review staff would complete their reviews and collect the additional data and present 

them to the Commissioner and the Acting Director of CDER some time in February. 

Review staff within both Offices of Drug Evaluation III and V later noted in their completed reviews 

of the Plan B OTC switch application that they were told at this meeting that the decision on the 

Plan B application would be made at a level higher than the offices of drug evaluation. 

January 16, 2004 A teleconference was held between review staff from the Office of Drug Evaluation V and the 

sponsor. According to meeting minutes, review staff informed the sponsor that a meeting was held 

with CDER management, including the Acting Director of CDER and the Director and Deputy 

Director of the Office of New Drugs, in which “some issues” were raised that would require review 

staff to “provide additional information and have additional discussions with CDER upper 

management.” Minutes also noted that review staff told the sponsor they would not be discussing 

labeling revisions at that time and that they had been instructed by CDER management to 

complete their written reviews regarding the OTC switch application. 

January 21, 2004 A memorandum from the Director of Office of Drug Evaluation V indicated that she was in 

agreement with the favorable assessment of review staff and the majority votes by members of 

the joint advisory committee. Her memorandum concluded that adequate data had been submitted 

to approve Plan B for OTC marketing with certain product-labeling modifications—such as

strengthening the message that Plan B is not for regular contraceptive use—included to address 

concerns raised at the public meeting and in the agency’s reviews. 

January 23, 2004 A meeting was held between FDA officials within the Office of New Drugs and the Offices of Drug 

Evaluation III and V and Barr Pharmaceuticals, Inc./WCC. According to meeting minutes, FDA 

officials told the sponsor that the decision on the application would be made at a level higher than 

the Offices of Drug Evaluation. The Director of the Office of New Drugs told the sponsor that such 

a high-level decision was not typical of CDER’s procedures for drug approvals. The minutes also 

noted that review staff within the Offices of Drug Evaluation were in the process of completing 

their reviews and would forward them with their final recommendations to high-level management. 

Meeting minutes also indicated that FDA officials told the sponsor that they would need to request 

a meeting directly with the Office of the Center Director or the Office of New Drugs to understand 

high-level management’s concerns. 

In addition, meeting minutes noted that FDA officials told the sponsor that the Office of the 

Commissioner and the Acting Director of CDER had raised concerns as to whether there were 

adequate data to establish that minors (i.e., those under 18 years of age) would use Plan B 

appropriately in the absence of a learned intermediary. Potential options that were suggested from 

FDA and CDER management included the possible need to (1) collect additional data, perhaps 

from another actual use study targeted to minors, or (2) to impose an age restriction on the OTC

sale of the product. 

Page 44 GAO-06-109 Initial FDA Decision on Emergency Contraceptive
Appendix III: Timeline of Major Plan B 

Events Related to the Initial OTC Switch

Application 

Date Event

February 2, 2004 Review staff within the Office of Drug Evaluation III requested that the sponsor reanalyze the 

adolescent data of the Plan B actual use study. According to the official request, staff asked for a 

“[s]ummary presentation of the Actual Use data from the participants in the less than 18 years of 

age subset, including comparisons to the older subset within the study.” 

February 13, 2004 FDA confirmed that it had extended the PDUFA goal date for a decision on the Plan B OTC switch 

application for 90 days due to the submission of the requested adolescent data from the actual 

use study by the sponsor. The extended PDUFA goal date was May 21, 2004. 

February 18, 2004 A briefing was held during which review staff within Offices of Drug Evaluation III and V presented 

their analysis of additional summary data to the Commissioner on the use and behavior of

adolescents in association with increased access to emergency contraceptive pills. Other

attendees included the Acting Deputy Commissioner for Operations and the Acting Director of 

CDER. According to meeting minutes, included in the presentation were the review staff’s

recommendations that Plan B have an OTC marketing status without restriction. The meeting 

minutes also noted that the Commissioner raised concerns regarding adolescents, including the 

potential for changes in future contraceptive behaviors and the potential benefits of counseling 

from a learned intermediary for younger adolescents. 

In addition, the meeting minutes noted that CDER was directed by the Commissioner to work with 

the sponsor on a marketing plan to limit the availability of Plan B in an OTC setting and to consider 

the most appropriate ages that should have OTC access restricted. The Commissioner requested 

a “rapid action” on the application. 

February 19, 2004 Review staff within the Offices of Drug Evaluation III and V met with the Acting Deputy 

Commissioner for Operations, the Acting Director of CDER, and the Director and the Deputy 

Director of the Office of New Drugs. According to a reviewer’s memorandum, in part, during this 

meeting, the Acting Deputy Commissioner for Operations expressed her and the Commissioner’s 

concerns regarding adolescents and the potential for adverse behaviors resulting from increased

access to Plan B. The Acting Director of CDER concurred with these concerns. 

February 22, 2004 This was the original PDUFA goal date for the initial Plan B OTC switch application. 

February 26, 2004 Barr Pharmaceuticals, Inc., completed acquisition of the marketing rights for Plan B from WCC. 

March 11, 2004 Barr Pharmaceuticals, Inc., submitted an amendment to its sNDA, proposing a dual-marketing 

strategy, making Plan B OTC for women 16 years of age and older and prescription only for 

women under 16 years of age. 

April 2, 2004 The Deputy Director of the Office of Drug Evaluation III completed her review of the Plan B OTC 

switch application and recommended that Plan B be approved for use as an emergency 

contraceptive in the OTC setting without age restriction. The review concluded there were

sufficient data on the safety and effectiveness of Plan B to approve its use in the OTC setting. 

April 22, 2004 The Director of the Office of New Drugs issued his review of the Plan B application and concurred 

with the recommendations of the offices of drug evaluation that the sponsor had provided

adequate data to demonstrate that Plan B could be safely, effectively, and appropriately used by 

women of childbearing potential for the indication of emergency contraception without a 

prescription. He recommended that this application be approved to permit availability of Plan B 

without a prescription and without age restriction. 

May 2, 2004 The Acting Director of CDER contacted the Director of the Office of Pediatric Therapeutics, within 

the Office of the Commissioner, via e-mail requesting assistance on language regarding cognitive 

development among adolescents. 

According to internal FDA e-mails, the Director of the Office of Pediatric Therapeutics responded 

that she would consult with another official with a background in developmental pediatrics and 

would follow up with “behavioral science information as to why one cannot extrapolate decision 

making on safety issues” from older populations to younger adolescents. 

Page 45 GAO-06-109 Initial FDA Decision on Emergency Contraceptive
Appendix III: Timeline of Major Plan B 

Events Related to the Initial OTC Switch

Application 

Date Event

May 3, 2004 According to internal FDA e-mails, the Director of the Office of Pediatric Therapeutics provided the 

Acting Director of CDER with information on brain development and the maturation of higher-order 

thinking among adolescents 10 years to 21 years of age. In her e-mail to the Acting Director, the 

Director of the Office of Pediatric Therapeutics included the statement that “[d]uring early 

adolescence (10-13) there is an emergence of impulsive behavior without the cognitive ability to 

understand the etiology of their behavior.” 

May 5, 2004 According to teleconference minutes, the Acting Director of CDER called Barr Pharmaceuticals, 

Inc., officials to inform them of the not-approvable action and asked permission to release the notapprovable letter. According to FDA regulations, without consent of the sponsor, the agency 

cannot publicly release data or information contained in an application before an approval letter is 

issued.f

Minutes noted that the Acting Director told sponsor officials that (with their permission) he would 

conduct a press interview to discuss the not-approvable action and the staff’s disagreement with 

the not-approvable action would be acknowledged publicly. 

May 6, 2004 FDA issued a not-approvable letter, denying Plan B OTC marketing status, citing a lack of

adequate data regarding safe use among younger adolescents. The letter also stated that FDA 

was not able to conduct a complete review of the dual-marketing strategy in the amendment to the 

sNDA because of the absence of the draft product labeling describing how Barr Pharmaceuticals, 

Inc., would comply with both the prescription and OTC labeling requirements in a single package. 

Source: GAO analysis of FDA data. 

a

See 21 U.S.C. § 355a(b), (c). FDA may request that manufacturers of new or already-marketed 

drugs conduct studies of their drugs in pediatric populations where it believes that such studies will 

lead to additional health benefits. Studies completed in accordance with FDA requirements entitle the 

manufacturer to an additional 6 months of marketing exclusivity. In its technical comments on the 

draft of this report, FDA stated that it did not ask for pediatric data for the prescription version of Plan 

B because the product’s physiological effects are the same in younger and older women, and 

because a health care practitioner is involved in dispensing prescription drugs. 

b

On September 23, 2005, the Commissioner of FDA, who was appointed on July 18, 2005, resigned 

from his position. He held the title of Deputy Commissioner from February 24, 2002, until March 26, 

2004, when he was named Acting Commissioner. Because he was Deputy Commissioner during 

most of the time covered by this report—for those events associated with the initial Plan B OTC 

switch application through the May 6, 2004, decision—we use the title of Deputy Commissioner for 

him in this report.

c

Behind-the-counter is defined as a classification of drug products that do not require a prescription 

but are also unlike OTC products in that there is a measure of clinical oversight in their use. For 

behind-the-counter products, pharmacists are able to intervene by advising patients on the product’s 

proper use and associated risks and by referring them to their physicians when appropriate. See 

Robert I. Field, “Support Grows for a Third Class of ‘Behind-the-Counter’ Drugs,” Pharmacy and 

Therapeutics, vol. 30, no.5 (2005): 260-261. 

d

FDA, in collaboration with various stakeholders, including representatives from consumer, patient, 

and health care provider groups and the pharmaceutical and biotechnology industries, has developed 

performance goals for the time to complete the review of an application submitted to the agency, 

which have been incorporated by reference into PDUFA. 

e

The Acting Deputy Commissioner for Operations was the Director of CDER when the initial Plan B 

OTC switch application was submitted in April 2003. She told GAO that she became the Acting 

Deputy Commissioner for Operations in March 2004, and that her role in the review of the initial Plan 

B OTC switch application was as a consultant to the Acting CDER Director. 

f

See 21 C.F.R. § 314.430(d)(1). 

Page 46 GAO-06-109 Initial FDA Decision on Emergency Contraceptive
Appendix IV: Acting Director of CDER’s 

Official Memorandum Explaining His Not- Appendix IV Approvable Decision, May 6, 2004 : Acting Director of CDER’s 

Official Memorandum Explaining His NotApprovable Decision, May 6, 2004 

The following is the official memorandum submitted to the record by the Acting 

Director of CDER to explain his decision on the initial Plan B OTC switch application. 

GAO has redacted information identifying specific persons as well as information not 

directly related to the review of the initial Plan B application.

Page 47 GAO-06-109 Initial FDA Decision on Emergency Contraceptive
Appendix IV: Acting Director of CDER’s 

Official Memorandum Explaining His NotApprovable Decision, May 6, 2004 

Page 48 GAO-06-109 Initial FDA Decision on Emergency Contraceptive
Appendix IV: Acting Director of CDER’s 

Official Memorandum Explaining His NotApprovable Decision, May 6, 2004 

Page 49 GAO-06-109 Initial FDA Decision on Emergency Contraceptive
Appendix V: Director of the Office of New Drugs’ 

Official Memorandum on His Decision on the Appendix V Plan B Application, April 22, 2004 : Director of the Office of New 

Drugs’ Official Memorandum on His Decision 

on the Plan B Application, April 22, 2004 

The following is the official memorandum submitted to the record by the Director of 

the Office of New Drugs to explain his decision on the initial Plan B OTC switch 

application. GAO has redacted information identifying specific persons as well as 

information not directly related to the review of the initial Plan B application. 

Page 50 GAO-06-109 Initial FDA Decision on Emergency Contraceptive
Appendix V: Director of the Office of New Drugs’ 

Official Memorandum on His Decision on the 

Plan B Application, April 22, 2004

Page 51 GAO-06-109 Initial FDA Decision on Emergency Contraceptive
Appendix V: Director of the Office of New Drugs’ 

Official Memorandum on His Decision on the 

Plan B Application, April 22, 2004

Page 52 GAO-06-109 Initial FDA Decision on Emergency Contraceptive
Appendix VI: Comments from the Food and Appendix VI: Comments from the Food and Drug Administration 

Drug Administration 

Page 53 GAO-06-109 Initial FDA Decision on Emergency Contraceptive
Appendix VI: Comments from the Food and

Drug Administration 

Page 54 GAO-06-109 Initial FDA Decision on Emergency Contraceptive
Appendix VI: Comments from the Food and

Drug Administration 

Page 55 GAO-06-109 Initial FDA Decision on Emergency Contraceptive
Appendix VI: Comments from the Food and

Drug Administration 

Page 56 GAO-06-109 Initial FDA Decision on Emergency Contraceptive
Appendix VII: 

St

GAO Contact and 

aff Acknowledgments

Page 57 GAO-06-109

Appendix VII: GAO Contact and Staff 

Acknowledgments 

GAO Contact Marcia Crosse, (202) 512-7119 or crossem@gao.gov

In addition to the contact named above, Martin T. Gahart, Assistant 

Director; Cathleen Hamann; Julian Klazkin; Gay Hee Lee; and Deborah J. 

Miller made key contributions to this report. 

Initial FDA Decision on Emergency Contraceptive

Acknowledgments 

(290410) 
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